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Review

Contribution of SDF-1α/CXCR4 Signaling to Brain Development and Glioma Progression

Jiang Z.a · Zhou W.b · Guan S.b · Wang J.b · Liang Y.b

Author affiliations

aDepartment of Neurosurgery, Qilu Hospital, Shandong University, and bDepartment of Radiotherapy, Cancer Centre, Qilu Hospital, Shandong University, Jinan, PR China

Corresponding Author

Yemin Liang

Department of Radiotherapy, Cancer Centre

Qilu Hospital, Shandong University, 107 Wenhuaxi Street

Jinan, Shandong Province 250012 (PR China)

Tel. +86 531 8216 9821, E-Mail dryeminliang@yahoo.cn

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Neurosignals 2013;21:240-258

Abstract

The SDF-1α/CXCR4 signaling maintains central nervous system homeostasis through the interaction with the neurotransmitter and neuropeptide systems, the neuroendocrine systems. Recently, the SDF-1α/CXCR4 signaling has been reported to present nonrandom distribution in brain development and glioma progression, which exerts differential regulations on the assembly, differentiation, and function of neural precursors, neurons, glial cells, as well as glioma cells. In the present review, we highlight current knowledge about multiple molecular signaling pathways associated with the SDF-1α/CXCR4 signaling in glioma. Not only is the expression of CXCR4 a key determinant of glioma progression, but SDF-1α is essential for site-specific invasive or metastatic processes. SDF-1α is the switch of the SDF-1α/CXCR4 signaling from the endocrine loop to the autocrine and/or local paracrine loop in glioma progression and brain development. Studies of SDF-1α/CXCR4 signaling in the field of brain development may provide valuable tactics for glioma treatment.

© 2012 S. Karger AG, Basel


Keywords

Chemokines · Cancer · Brain · Neuropathology ·


Introduction

Chemokines are small (8-14 kDa), secreted chemotactic proteins which are now the largest known cytokine family. Chemokines are classified into four subfamilies depending on the spacing of their first two cysteine residues: C, CC, CXC, and CX3C. Stromal cell-derived factor 1α (SDF-1α), also known as chemokine ligand 12 (CXCL12), is the only known ligand for G-protein-coupled, seven-span transmembrane chemokine receptor 4 (CXCR4) [1]. CXCR4 is also a target for human immunodeficiency virus (HIV) binding. The SDF-1α/CXCR4 signaling mediates many physiological processes including cell trafficking, angiogenesis, and embryogenesis. It controls the chemotaxis of hematopoietic stem cells homing to the bone marrow in adults. Recently, it has been established that this signaling is playing a critical role in tumor invasion and metastatic processes. CXCR4 is highly expressed on a number of cancer cells, including human lung, breast, melanoma, and colon cancer cells [1,2,3,4]. SDF-1 is also constitutively secreted in a variety of tissues representing the first destinations of tumor metastasis such as lung, liver, lymph node, bone marrow, and adrenal gland [2,5]. CXCR4 signaling in response to CXCL12 mediates actin polymerization and pseudopodia formation through calcium mobilization, β-arrestin recruitment, as well as ERK1/2 phosphorylation [2,6].

SDF-1 has three isoforms, α, β, and γ, which are different at the splicing level, not at the transcriptional level [7]. In adult rat brain, SDF-1α is the predominant one, present in astrocytes, microglia, as well as in neurons [8,9]. Banisadr et al. [8] reported that SDF-1α is found positive in normal cholinergic neurons, such as in the medial septum and substantia innominata, and in dopaminergic neurons, such as in the substantia nigra (SN) pars compacta and the ventral tegmental area.

CXCR4 is also present in astrocytes, microglia, and in neurons. CXCR4 is constitutively expressed in cholinergic, dopaminergic, and GABAergic neurons [10,11]. Although CXCR4 is widely expressed in neurons in the neocortex, hippocampus, basal nuclei, thalamus, brain stem, and cerebellum [12], the areas of highest expression are subcortical regions and the limbic system [13]. As the limbic system has memory function, CXCR4 - the major co-receptor for the HIV-1 glycoprotein 120 (gp120) - plays a vital role in the development of HIV-related dementia [13,14]. Van der Meer et al. [15] reported that the onset time of CXCR4 expression is between 3.5 and 4.5 years in the fetal human brain. Ligand-dependent or -independent internalization of CXCR4 is regulated by a C-terminal cytoplasmic domain between amino acids 336 and 342 [16]. CXCR7 has recently been identified as another receptor for SDF-1α [17]. Further study is needed about the relationship between CXCR4 and CXCR7, cooperative or independent in SDF-1-dependent neuronal development [18].

Neuropathological Aspects of the SDF-1α/CXCR4 Axis in Glioma

Prevalence and Histopathological Features in Glioma

We used both semiquantitative RT-PCR and real-time quantitative RT-PCR assays to determine mRNA expressions of CXCR4 and SDF-1α in 76 astrocytomas and 10 normal brain tissues [19]. All of the astrocytomas exhibited high CXCR4 mRNA levels compared with normal brain samples. Moreover, the expression of CXCR4 increased with increasing tumor grades. Sehgal et al. [20] reported that CXCR4 was overexpressed in glioblastoma multiforme (GBM), with 57% of the primary specimens and 88% of the cell lines. CXCR4 protein expression is significantly higher in gliomas of grade III and IV than in gliomas of grade II [21,22]. Our results, together with recent findings [22,23,24,25], manifested that CXCR4 expression correlates directly with the degree of glioma malignancy. Additionally, glioma cells with overexpression of CXCR4 were observed to develop rapidly growing and lethal xenografted tumors in mice [25]. Furthermore, CXCR4 is also related with angiogenesis and vasculogenesis. CXCR4 expression is observed in neovessel endothelial cells [21]. Primary human glioma samples with overexpression of CXCR4 showed high-density microvessels [25]. Patients with CXCR4-positive tumors demonstrated a lower rate of 3-year postoperative survival than those with CXCR4-negative tumors [25].

Although most gliomas exhibit CXCR4 expression, only part of the gliomas, especially high-grade gliomas, exhibit positive expression of SDF-1α. Barbero et al. [26] reported that CXCR4 was expressed in all tumors analyzed, while SDF-1α was expressed only in two tumor tissues. SDF-1α expression increases with tumor grade [21]. In our study [19], 16 samples of WHO grade II exhibited no expression of SDF-1α mRNA, while 90.0% of GBMs exhibited high expression of SDF-1α. The overexpression of SDF-1α is evident mainly in the pseudopalisading cells and the proliferating microvessels [27]. In low-grade gliomas, positive expression of SDF-1α protein is a predictive factor for a significantly shorter time to tumor progression [28,29]. Also, in 40 low-grade oligodendrogliomas and oligoastrocytomas, the prognostic value of SDF-1α expression, either on tumor or on endothelial cells, is associated with a significantly shorter time to tumor progression [30]. SDF-1α mediates normal structure formation, as shown in the brain development discussed below. Furthermore, SDF-1α also takes part in maintaining the blood-brain barrier. SDF-1α plays an anti-inflammatory role, which limits inflammation by localizing mononuclear infiltrates to the perivascular space [31]. In addition, SDF-1α stimulates brain capillary endothelial cells to tube-like structure formation [32].

There is a marked co-localization of CXCR4 and SDF-1α in tumor cells, especially in regions of angiogenesis and degenerative, necrotic, and microcystic changes, which demonstrates the close relationship with angiogenesis and immune response [21,33]. Additionally, GBM cells exhibited low expression of SDF-1α/CXCR4 in an aerophilic condition and a high expression of SDF-1α/CXCR4 in a hypoxic condition [27].

Interestingly, the SDF-1α/CXCR4 signaling also mediates the nonrandom formation of Scherer's secondary structures, which is unique in GBM patients [34]. CXCR4 was widely expressed in tumor cells around neurons and blood vessels. SDF-1α, unlike CXCR4, was selectively expressed in Scherer's secondary structures, namely neurons, blood vessels, subpial regions, and white matter tracts [34]. Not only is the expression of CXCR4 a key determinant of tumor progression, but SDF-1α is also essential for site-specific invasive or metastatic processes [4,35,36,37]. Although tumor cells showed low levels of SDF-1α expression as compared with CXCR4, SDF-1α exhibits peak levels of constitutive expression in regions or organs representing the first destination of cancer invasion or metastasis [4,34,35,36,37]. Previous studies have demonstrated that recombined human SDF-1α could stimulate the proliferation of a variety of tumor cells in vitro [38,39]. But re-expression of endogenous SDF-1α in colorectal or breast carcinoma cells inhibited metastatic tumor formation in mice [4,37]. SDF-1α expression in tumor cells, in summary, is the switch of the SDF-1α/CXCR4 signaling from the endocrine loop to the autocrine and/or local paracrine loop. Cancer cells, lacking expression of SDF-1α but maintaining expression of CXCR4, follow the endocrine SDF-1α gradients to remote regions. Cancer cells, maintaining expression of SDF-1α and CXCR4, dwell and proliferate in the primary region, in the autocrine and/or local paracrine loop.

Roles of SDF-1α/CXCR4 in Brain Development

Neurogenesis occurs only in discrete regions of the adult brain: the subventricular zone (SVZ) and the subgranular zone [40]. During brain development, SDF-1α exerts differential regulation on distinct cell populations, including neuronal progenitor and precursor cells, glutamatergic and GABAergic neurons, and glial cells [41]. Tissir et al. [42] studied the expression of CXCR4 and SDF-1α mRNA during mouse brain development. CXCR4 is widely expressed in neuronal progenitor cells and subpopulations of differentiating neurons, including cerebellar external granule cells, cranial nerve nuclei, and telencephalic preplate. But CXCR4 expression tapers off during brain development. In contrast, SDF-1α expression is scattered only in the telencephalic intermediate zone in embryos and in the meninges in adults [42].

Neuronal Precursor Cells

Neural stem cells (NSCs) are a subset of self-renewing and multipotent neural progenitor cells (NPCs) that generate the main phenotypes of the nervous system. Among the various chemokine receptors in adult mouse NSCs, CXCR4 exhibits the highest mRNA levels and functionality in chemotaxis assays and calcium signaling experiments [43]. SDF-1α induces human NPC migration through upregulation of inositol 1,4,5-triphosphate, extracellular signal-regulated kinases (ERK) 1/2, Akt, c-Jun N-terminal kinase, and intracellular calcium and downregulation of cAMP [44]. Although the SDF-1α/CXCR4 signaling promotes the migration of NPCs, it reversibly prevents NPCs from proliferation, keeping NPCs in a quiescent state [45]. SDF-1 regulates the proliferation of progenitors, possibly through a mechanism involving connexin 43-mediated intercellular coupling [41]. Li et al. [46] demonstrated that SDF-1α alone could neither stimulate the self-renewal of NPCs, nor enhance bFGF/EGF-induced proliferation of NPCs. But the CXCR4 antagonist AMD3100 blocks the bFGF/EGF-induced expansion of NPCs through modulating their cell cycling.

The SDF-1α/CXCR4 signaling directly regulates the migration of neuronal precursor cells, including cortical Cajal-Retzius cells, cerebellar granule precursor cells and dentate gyrus (DG) granule precursor cells [47]. (1) Cajal-Retzius cells are reelin-producing neurons, located in the human embryonic deep marginal zone. SDF-1α secreted by the leptomeninges is indispensable to the tangential migration of Cajal-Retzius cells along the cortical surface [48,49]. Mutations in CXCR4 result in Cajal-Retzius cells ectopically placed in the deeper cortical layers during neocortical development [49]. However, Stumm et al. [50] argued that SDF-1α in the leptomeninx does not selectively regulate Cajal-Retzius cells, but regulates interneuron precursor migration from the basal forebrain to the neocortex. In the postnatal CA1 stratum lacunosum-moleculare, SDF-1α suppresses spontaneous firing in Cajal-Retzius cells via hyperpolarization, which is involved in the information processing of the stratum lacunosum-moleculare [51]. (2) The SDF-1α/CXCR4 signaling also promotes the migration of cerebellar granule precursor cells from the upper rhombic lip and the external germinal layer to the internal granular layer, as well as the proliferation of granule cells [52,53,54]. Silencing of the SDF-1α gene results in loss of external germinal layer cells' chemotactic ability in the meninges. This suggests the predominant role of SDF-1α in cerebellar neuronal migration [52]. (3) In DG development, SDF-1α directly attracts DG progenitor migration, especially first to a transient subpial neurogenic zone [55,56]. In mice deficient in CXCR4, mitotic cells in the migratory stream and in the DG are decreased, and neurons differentiate prematurely before reaching their target [57]. However, Li et al. [56] found that the final settlement of the DG granule precursor cells at the subgranular zone is not dependent on the SDF-1α/CXCR4 signaling. In addition, SDF-1α guides the growth of perforant fibers linking the entorhinal cortex with the DG in a neural circuit [58]. During the early postnatal period, SDF-1α is expressed in Cajal-Retzius cells on the upper and lower blades of the dentate and in the maturing dentate granule neurons, as well as in the meninges [59]. Bhattacharyya et al. [60] observed that SDF-1α regulates GABAergic inputs from basket cells to the pool of dividing NPCs in the postnatal DG.

Glutamatergic and GABAergic Neurons

Functioning of the cerebral cortex requires the coordinated assembly of two classes of cortical neurons: excitatory projection neurons (e.g. glutamatergic neurons) and inhibitory local circuit neurons (e.g. GABAergic interneurons) [61]. Cortical glutamatergic neurons derive from the ventricular zone (VZ) of the dorsal telencephalon, while 65% of cortical GABAergic neurons (Dlx1/2-positive and Mash1-positive) derive from the VZ and SVZ of the dorsal forebrain, and the other 35% (Dlx1/2-positive and Mash1-negative) derive from the ganglionic eminence of the ventral forebrain [62,63]. The SDF-1α/CXCR4 signaling regulates these highly stereotyped routes. SDF-1α/CXCR4 also mediates the interaction between glutamatergic neuron precursors and GABAergic interneurons in the intermediate zone (IZ)/SVZ [64]. In addition, CXCR4 promotes neuronal survival by inhibiting the E2F-dependent apoptotic pathway, maintaining neurons in a highly differentiated and quiescent state [65].

GABAergic interneurons are divided into several subtypes, according to their expression of parvalbumin, calbindin, calretinin, and somatostatin [66,67]. CXCR4 is required for the proliferation, differentiation, and layer-specific distribution of interneuron subtypes [41,66]. Constitutive deletion of CXCR4 signaling leads to disorganized migratory streams and premature cortical plate invasion of GABAergic interneurons, which disrupts their laminar and regional distribution [61,66,68]. In the developing telencephalon, cortical GABAergic neurons require SDF-1α to maintain their tangential migration to the IZ/SVZ [69,70]. During invasion of the cortical plate, these neurons change the tangential course to the radial one, accompanied by a decrease of SDF-1α in the IZ/SVZ [68,69]. In addition, SDF-1α/CXCR4 increases the production and neurite localization of GABA and promotes the maturation of GABAergic neurons through downstream activation of ERK1/2, Egr1, and GAD67 (a 67-kDa form of glutamic acid decarboxylase) [71].

SDF-1α acts in the generation of axons and dendrites (fig. 1). In cortical glutamatergic neurons, SDF-1α enables the elongation and branching of axons [41]. Similarly, SDF-1α regulates both path finding and elongation of axons in the developing hippocampus and cerebellum [72,73,74]. SDF-1 regulates axon development, without affecting the other neurites, via dendrite-selective trafficking of CXCR4 in endosomes [75]. At an early developmental stage of hippocampal neurons, CXCR4 at the leading edge of growing neurites stimulates axonal branching but reduces growth of cone number and axonal outgrowth. CXCR4 is broadly distributed along axons and dendrites during the maturation of neurons [73]. In cultured cerebellar granule neurons, a low concentration of SDF-1α promotes axon elongation via the Rho/mDia pathway, while a high concentration of SDF-1α inhibits axon elongation via the Rho/ROCK pathway [72]. In addition, SDF-1α/CXCR4 is essential for placode assembly and sensory axon path finding in the olfactory system [76].

Fig. 1

SDF-1 selectively regulates axon development (see [41,72,73,74,75]).

http://www.karger.com/WebMaterial/ShowPic/188803

SDF-1α modulates synaptic transmission and electrical activity. Limatola et al. [77] observed a pronounced expression of CXCR4 in cerebellar glial, granule, and Purkinje cells. SDF-1α provokes Ca2+ transients in both granule cell bodies and neuronal processes. In Purkinje neurons, SDF-1α triggers a slow inward current followed by an increase of both the intracellular Ca2+ level and spontaneous synaptic activity [77]. Also, in Purkinje neurons, SDF-1α restrains evoked excitatory postsynaptic currents (EPSC) stimulated by the parallel fibers [78]. Interestingly, both activities of SDF-1α mentioned above in Purkinje neurons are mediated by glutamate release from glial cells [77,78]. However, Guyon et al. [79] reported that SDF-1α directly modulates voltage-dependent currents of the action potential in mammalian neuronal cells. Furthermore, Liu et al. [80] found that synchronized spontaneous Ca2+ spikes among hippocampal neurons are suppressed by SDF-1α through the inhibition of the cAMP pathway. Synchronized Ca2+ spikes, arising from periodic burst firing of action potentials, participate in the development and plasticity of neuronal circuitry [80]. Giant depolarizing potentials (GDPs) play a vital role in the establishment and maturation of synaptic connections during the early development of the hippocampus [81]. GABA has an excitatory action on GDPs, while glutamate has an inhibitory action on them. Kasiyanov et al. [82] found that SDF-1α decreases GDP firing induced by GABA in the immediate postnatal period of the hippocampus. In newly formed DG granule cells, CXCR4 is tonically activated and downregulated by endogenous SDF-1α, which is postulated to be important to neurogenesis-dependent long-term memory in the adult hippocampus [83].

In addition, the SDF-1α/CXCR4 signaling is required for nuclei formation. Zhu et al. [84] showed that SDF-1α regulates the migration of mossy-fiber projecting precerebellar neurons tangentially from the lower rhombic lip to the hindbrain, forming precerebellar nuclei. SDF-1α also regulates the anteroventrally directed migration of the pontine neurons to the pons, forming the pontine nuclei [84].

Glial Cells

The SDF-1α/CXCR4 signaling regulates migration and proliferation of oligodendrocyte precursors (OLPs) as well as neural precursors [85]. CXCR4 mediates migratory response of neonatal OLPs, which co-expresses with platelet-derived growth factor receptor-α (PDGFR-α). The expressions of CXCR4 and PDGFR-α receptors also decreases during OLP differentiation [85]. Further, SDF-1α dose-dependently increases OLP proliferation and myelin production [86]. Multiple sclerosis is an autoimmune disease in which myelin sheaths around the axons are demyelinated with loss of oligodendrocytes. During demyelination, the activated astrocytes and microglia enhance the secretion of SDF-1α, which in turn promotes the differentiation of OLPs into oligodendrocytes for remyelination [87].

CXCR4 is also widely expressed on glial cells, including astrocytes and oligodendrocytes. Astrocytes act as structural and metabolic support for neurons. Their anatomical position between blood vessels and neurons makes them an interface for energy metabolism and gliotransmitter regulation [88,89]. SDF-1α stimulates a series of intracellular and extracellular events, such as the release of Ca2+, TNF-α, and prostaglandins, which eventually leads to glutamate release [88].

Roles of SDF-1α/CXCR4 in Brain Function

SDF-1α/CXCR4 Axis and Hypothalamus/Pituitary Axis

The interaction of SDF-1α/CXCR4 plays an important role in the regulation of the hypothalamus/pituitary axis. CXCR4 is expressed in normal anterior pituitary, as well as in the hypothalamus. SDF-1α stimulates both prolactin and growth hormone (GH) production, secretion, and cellular proliferation [90,91,92]. Barbieri et al. [90] and Florio et al. [91] found that the SDF-1α-induced GH release is a solely Ca2+-dependent process, while SDF-1α-induced proliferation of GH4C1 rat pituitary adenoma cells is dependent on both the Ca2+-independent stimulation of ERK1/2 activity and the Ca2+-dependent activation of Pyk2 and large-conductance Ca2+-activated K+ channels (BKCa).

Hypothalamic gonadotropin-releasing hormone (GnRH) neurons control pituitary gonadotropin secretion and gametogenesis. During development, these neurons migrate from the olfactory placode to the hypothalamus [93]. In the process, the SDF-1α/CXCR4 signaling does not function as guidance in the directional outgrowth of olfactory axons, but it guides GnRH-1 neuronal migration and modulates GnRH-1 production in these neurons [94,95]. Similarly, knockdown of SDF-1α or CXCR4 in GnRH3 neurons of the zebrafish influenced GnRH3 neuron migration. It also altered directional outgrowth of neuronal axons, losing its characteristic lateral crossing at the anterior commissure and optic chiasm [93].

In the lateral hypothalamus, CXCR4 is found in neurons secreting melanin-concentrating hormone (MCH), which contributes to feeding behavior regulation [8,96]. SDF-1α may control MCH neuron excitability indirectly through glutamate/GABA release and directly through voltage-dependent membrane currents [96].

SDF-1α/CXCR4 also takes part in the regulation of the hypothalamo-neurohypophysial system. SDF-1α is localized in the arginine vasopressin/antidiuretic hormone (AVP/ADH) neurons, including the hypothalamic supraoptic nucleus, the paraventricular nucleus, and the posterior pituitary [8,97,98]. SDF-1α modulates central water balance through the electrophysiological activities of AVP/ADH neurons and consequently AVP/ADH release, but not dependent on peripheral modifications of kidney water balance [97,98].

SDF-1α/CXCR4 Axis and Nigrostriatal Dopamine System

Parkinson's disease (PD) is a degenerative disorder resulting from the death of dopamine-generating cells in the SN. However, the cause of cell death is unknown. Shimoji et al. [99] reported that the SDF-1α/CXCR4 signaling is involved in the inflammation and proliferation of microglia, which may contribute to the death of dopamine-generating neurons. Furthermore, the pathological expression of SDF-1α and CXCR4 in the SN of PD patients was much higher than in normal controls in spite of loss of dopamine neurons [99]. Skrzydelski et al. [100] used patch clamp to record the electrophysiological activities of dopamine neurons in the SN. SDF-1α stimulated neurons to dopamine release by a depolarization and an increased action potential frequency as well as by a change from a tonic firing pattern of depolarization to a burst firing pattern. Guyon et al. [101] reported that SDF-1α acts directly on the membrane conductance and high voltage-activated Ca2+ currents of dopamine neurons in the SN. When Ca2+ currents were activated by the depolarization of KCl, lower SDF-1α concentrations were needed for dopamine release. CXCR4 is also expressed on non-dopamine cells in the SN. In these cells, SDF-1α indirectly stimulates dopamine neurons by presynaptic mechanisms, including an increased frequency of spontaneous and miniature GABA(A) postsynaptic currents, a glutamatergic inward current, and an outward G protein-activated inward rectifier current [102]. In addition, CXCR4 participates in the regulation of the striatal function. Trecki et al. [11] detected the co-localization of CXCR4 and D1 dopamine receptors by cholinergic and GABAergic neurons in the caudate putamen and lateral shell of the nucleus accumbens. Rats improved their behavior both in the cylinder test and amphetamine-induced rotation test after mesenchymal stem cell (MSC) transplantation [103]. Wang et al. [103] attributed the neuroprotective effects of MSC dopaminergic neurons partly to the anti-apoptotic effects of SDF-1α.

SDF-1α/CXCR4 Axis and Opioids/Cannabinoids

The SDF-1α/CXCR4 signaling has also been confirmed to participate in heterologous desensitization. SDF-1α can influence the pharmacodynamic action of neuronal active agents, such as the opioids and cannabinoids. A similar pattern of expression is found for CXCR4 and µ-, ĸ-, and δ-opioid receptors in the brain, including the cingulate cortex, hippocampus, and periaqueductal gray (PAG) [104,105,106,107]. As is known, the PAG is a brain region in charge of pain signal processes, a target which many analgesic compounds act on [108]. The SDF-1α/CXCR4 axis expressed by the immune cells downregulates the electrophysiological activity of µ-, ĸ-, and δ-opioid receptors on the PAG [104,109]. Although morphine reduces input resistance by hyperpolarization, SDF-1α blocks morphine's electrophysiological effects on the PAG neurons [104]. Heterologous desensitization induced by SDF-1α blocks the analgesic action of opioid receptors, which enhances the perception of pain at inflammatory regions [104,107,109]. However, this heterologous desensitization is bidirectional. Evidence demonstrates that opioid receptors are also able to cross-desensitize CXCR4 [107,110]. Opioid receptors interact on normal CXCR4 receptors in different ways, depending on opioid receptors' subtypes [110]. In the control of bidirectional heterologous desensitization, apart from target receptor phosphorylation, the action of downstream signaling molecules, such as protein kinase A (PKA) or PKC, inhibits the coupling of GPCRs with the target receptor [111]. Activation of SDF-1α/CXCR4 in the PAG also interferes with the analgesic effects of the cannabinoid receptor agonist, an aminoalkylindole, WIN55,212-2 [112]. In addition, SDF-1α blocks hypothermia induced by WIN55,212-2 in the preoptic anterior hypothalamus [113]. But such an effect does not extend to other opioid medications such as buprenorphine. The SDF-1α/CXCR4 signaling does not influence the antinociceptive effect of buprenorphine. Conversely, buprenorphine appears to be more effective at high levels of SDF-1α in neuroinflammatory conditions [108].

SDF-1α/CXCR4 Axis and Serotonin System

The serotonin (5-hydroxytryptamine, 5-HT) system is closely related with depression. Over 70% of serotonin neurons co-localize with SDF-1α and CXCR4 in the rat dorsal raphe nucleus [114]. SDF-1α indirectly modulates 5-HT neurotransmission via presynaptic enhancement of GABA and glutamate release. SDF-1α raises the frequency of spontaneous inhibitory and excitatory postsynaptic currents (sIPSC and sEPSC) as well as the amplitude of sIPSC in 5-HT neurons [114]. Further study about the relationship between the SDF-1α/CXCR4 axis and the serotonin system may help cure depression associated with disorders of immune function.

Others

CXCR4 is also implicated in autonomic dysfunction, such as gastrointestinal dysfunction. Physiological studies [115] demonstrate that nano-injection of SDF-1α into the dorsal vagal complex of the hindbrain resulted in a significant decrease of gastric motility. In the development of vertebrate central nervous system (CNS), SDF-1α/CXCR4 helps direct the ventral axon trajectory of spinal motor neurons (vMNs) [116]. In the absence of CXCR4, mice developed with impaired limb innervation and myogenesis [117].

Alzheimer's disease (AD) is a well-characterized disease with cognitive decline involving two classic abnormal structures called plaques and tangles. Reduced SDF-1α levels were found in AD patients. Furthermore, the chronic treatment of SDF-1α antagonist results in similar cognitive deficits as in AD [118]. Short-term exercise showed a significant increase in SDF-1α, which may improve cognition [119]. In stroke, isoforms of SDF-1 play distinct roles during cerebral ischemia [120]. SDF-1α/CXCR4 recruits stem cells from the peripheral blood and mediates the repair and neoangiogenesis of ischemia regions [121,122,123].

Molecular Signals Associated with the SDF-1α/CXCR4 Axis in Glioma

SDF-1α/CXCR4 Axis and VEGF

Neuronal cells increase SDF-1α production upon the exposure of vascular endothelial growth factor (VEGF) [34]. VEGF induces SDF-1α and CXCR4 production by endothelial cells, which bind angiogenesis and chemotaxis together [29,34,124,125]. The interaction between SDF-1α and CXCR4 in endothelial cells enlarges the process of angiogenesis by inducing more VEGF secretion [125,126,127,128]. VEGF expression also upregulates SDF-1α and CXCR4 production in human glioma cells [129]. Interestingly, activation of chemokine receptor CXCR4 in malignant glioma cells also contributes to the high level of VEGF produced by malignant glioma cells [23]. These data exhibit a positive-feedback loop in which VEGF induces SDF-1α and CXCR4 production by endothelial cells and glioma cells, and in turn the SDF-1α/CXCR4 signaling magnifies VEGF expression by these cells (fig. 2). These findings suggest that the interaction between SDF-1α/CXCR4 and VEGF might play a vital role in tumor vasculogenesis and angiogenesis.

Fig. 2

The positive feedback loop between SDF-1α/CXCR4 and VEGF (see [23,29,34,124,125,126,127,128,129]).

http://www.karger.com/WebMaterial/ShowPic/188802

SDF-1α/CXCR4 Axis and HIF-1α

The CXCR4 receptor was found co-localized with HIF-1α in glioma cells around areas of necrosis, which suggested its correlation with hypoxia [124]. Hypoxia stimulates CXCR4 production by the activation of HIF-1α in tumor cells and the secretion of VEGF in human brain microvascular endothelial cells (HBMECs) [124]. Loss of function of von Hippel Lindau (VHL), which is required for oxygen-dependent degradation of HIF-1α, is associated with increased expression of CXCR4 and SDF-1α [130]. The hypoxia-induced release of SDF-1α is regulated not by p53, but by TGF-β-dependent HIF-1α [131]. Hypoxia is a key factor in determining NSC tropism to glioma. Hypoxia enhances the self-renewal capacity and inhibits the differentiation induction of the CD133-positive human glioma-derived cancer stem cells through activation of HIF-1α [132]. The SDF-1α/CXCR4 signaling mediates increased NSC-to-glioma tropism under hypoxia [133].

SDF-1α/CXCR4 Axis and TNF-α

The SDF-1α/CXCR4 signaling controls glutamate release from astrocytes via TNF-α and subsequently regulates glia-glia and glia-neuron communication (fig. 3) [134,135]. TNF-α, in turn, induces production of CXCR4 at both the mRNA and protein levels in human and simian astrocytes as well as in glioma cells [136,137]. With the cooperation of microglia, enhanced release of SDF-1α-induced TNF-α forms an autocrine or paracrine loop, which may cause the derangement of glial communication [134]. As for human endothelial cells, TNF-α has a biphasic effect on CXCR4 expression, with early inhibition and late induction [138]. Furthermore, TNF-α augments expression of CXCR4 on bone marrow-derived hMSCs, which elevates SDF-1α-induced migration of hMSCs to intracranial gliomas [139]. But Han et al. [140] reported that CXCR4 expression is reduced by exposure to TNF-α in primary mouse astrocytes. These findings suggest that TNF-α might play multiple roles in the regulation of the SDF-1α/CXCR4 axis among different cell types.

Fig. 3

SDF-1α/CXCR4 axis and TNF-α (see [134,135,136,137,138]).

http://www.karger.com/WebMaterial/ShowPic/188801

SDF-1α/CXCR4 Axis and bFGF

CXCR4 is shown to be enhanced upon exposure to basic fibroblast growth factor (bFGF) in malignant glioma cells as well as in endothelial cells [141]. Conversely, SDF-1α treatment inhibits the proliferation of endothelial cells induced by bFGF and prolongs the survival of endothelial cells [141]. These results suggested that the interaction of SDF-1α/CXCR4 and bFGF may modulate the cross talk between glioma cells and endothelial cells.

SDF-1α/CXCR4 Axis and Interleukins

The inflammatory cytokine IL-1β has recently been reported to mediate pathologic relocation of SDF-1α early before the disruption of the blood-brain barrier in multiple sclerosis [142]. In human astrocytoma cells, CXCR4 protein expression is increased after treatment of IL-1β [136]. Secretion of IL-6 enhances surface expression of CXCR4 and subsequently promotes SDF-1-dependent chemotaxis in astrocytes, which is involved in reactive gliosis and HIV-related dementia [143]. On the other hand, SDF-1α induces production of IL-8 in human astrocytoma cells [136]. Furthermore, CD133-positive glioma cells secrete more IL-8 than negative ones [144]. The lipoxygenase inhibitor Nordy, a synthetic chiral compound of nordihydroguaiaretic acid, diminishes CXCR4 expression in glioma cells and reduces tumor formation in mice [25]. In addition, Nordy significantly suppresses SDF-1α-induced production of angiogenic factors, IL-8 and VEGF, in glioma [145].

SDF-1α/CXCR4 Axis and C3a

Complement-derived anaphylatoxin C3a plays pathologically paradoxical roles in the CNS. C3a has anti-inflammatory functions, such as neurotrophin production and neurotoxicity prevention, as well as proinflammatory functions [146]. Furthermore, C3a also has physiological functions of neurogenesis and neuroprotection. Although C3a alone does not have a chemotactic ability in NPCs, it facilitates NPC migration at low levels of SDF-1α, while it inhibits NPC migration at high levels of SDF-1α [147]. Similarly, C3a restrains neuronal differentiation of NPCs in the presence of SDF-1α, while it promotes NPC differentiation without SDF-1α [147].

SDF-1α/CXCR4 Axis and Matrix Metalloproteinases

SDF-1α augments the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), but not the other MT-MMPs, MMP-2 or MMP-9 [148]. The SDF-1α-induced invasiveness of glioma cells is suppressed after silencing of MT2-MMP [148]. Leucine-rich repeats containing 4 (LRRC4) plays an inhibitory role on the progression of gliomas. Overexpression of LRRC4 inhibits SDF-1α/CXCR4 downstream molecules, such as ERK1/2 and Akt, and then proMMP-2 activation [149].

SDF-1α/CXCR4 Axis and Dipeptidyl Peptidases

Dipeptidyl peptidase-IV (DPP-IV, CD26) is a serine protease expressed on the surface of most cell types and is associated with immune regulation, signal transduction, and apoptosis. The increase of CXCR4 expression parallels with the rise of DPP-IV expression and activity in higher-grade gliomas, which suggests a potential relationship between DPP-IV and SDF-1α/CXCR4 [150]. Further studies [151,152] demonstrated that CD26/DPP-IV has the ability to cleave SDF-1α at its position 2 proline.

SDF-1α/CXCR4 Axis and BDNF

Brain-derived neurotrophic factor (BDNF) downregulates the expression of CXCR4 in the brain by internalization [153,154]. Furthermore, it is assumed that downregulation of CXCR4 partly explains the neuroprotective function of BDNF against HIV envelope protein gp120 toxicity [153,154]. The modulatory role of BDNF in CXCR4 expression occurs only in mature animals [154].

SDF-1α/CXCR4 Axis and HGF/c-Met Axis

Nuclear factor-ĸB (NF-ĸB) mediates a cross talk between the SDF-1α/CXCR4 and HGF/c-Met axes in glioma migration [155]. SDF-1α and CXCR4 production are enhanced upon exposure to hepatocyte growth factor (HGF) in glioma cells [156]. HGF-induced upregulation of SDF-1α/CXCR4 occurs through a NF-ĸB-dependent mechanism. HGF stimulates nuclear translocation of NF-ĸB by phosphorylation and degradation of IĸB-α [155]. It is interesting to find that knock down of NF-ĸB suppresses CXCR4 expression induced by HGF but not by hypoxia alone. But this suppression persists with hypoxia accompanied by HGF [155].

SDF-1α/CXCR4 Axis and Fractalkine/CX(3)CL1

The chemokine fractalkine/CX(3)CL1 and its cognate receptor, CX3CR1, play a role in atherogenesis and neuroprotection. SDF-1α increases cleavage of fractalkine from neurons through the stimulation of the inducible metalloproteinase ADAM-10 and -17 [157]. In addition, SDF-1α also upregulates expression of the fractalkine gene [157]. It is assumed that the interaction between SDF-1α and fractalkine contributes to neuroprotection of cortical neurons by modulating microglial neurotoxic properties [157].

SDF-1α/CXCR4 Axis and Prostaglandins

The cross talk between SDF-1α/CXCR4 and prostaglandins modulates the pathogenic network responsible for neuronal toxicity [158]. HIV-1 envelope gp120 stimulates cyclooxygenase (COX)-2 expression in astrocytoma cells via NF-ĸB [159]. In human astrocytes, SDF-1α induces production of COX-2 and secretion of prostaglandin E2 (PGE2) also via NF-ĸB [158]. Culture supernatants from SDF-1α-treated astrocytes inhibit viability of tumor cells, and COX inhibitors prevent this toxicity [158].

Others

Src homology 2 domain-containing phosphatase 2 (SHP2), encoded by PTPN11, is a non-receptor protein-tyrosine phosphatase. It is regarded as a proto-oncogene involved in tumor survival, proliferation, migration, and differentiation. SDF-1α induces phosphorylation of the tyrosine phosphatase SHP2, which contributes to the guidance of granule cell migration during cerebellar development [160]. SDF-1α induces plasminogen activator inhibitor-1 (PAI-1) expression in human glioma cells, which is required for activation of Gα(i), ERK [161]. In addition, CXCR4 is repressed by the Notch ligand δ-like 4 (Dll4) in endothelial cells [162].

Signal Transduction of the SDF-1α/CXCR4 Axis in Glioma

SDF-1α/CXCR4 Axis and PI3K-AKT-ERK

SDF-1α binding on the CXCR4 receptor activates both neurons and leukocytes through G(αi) activation [54]. Distinct from leukocytes, SDF-1α-induced activity in neurons is involved in Ca2+ flux, requiring predepolarization by KCl or pretreatment by glutamate [54]. SDF-1α provokes a raise of intracellular Ca2+ concentration and rapid phosphorylation of the mitogen-activated protein kinase (MAPK) cascade, specifically, extracellular signal-regulated kinase ERK1/2 in glioma cells [136,163,164]. In primary cultures of rat type-I astrocytes, SDF-1α selectively activates ERK1/2, but not p38 or stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) [165]. In these astrocytes, Pyk2 is regarded as an upstream component for the SDF-1α/CXCR4 signaling to ERK1/2 [165]. As to the ERK pathway, there are different responses to SDF-1α and the HIV glycoprotein gp120 in NPCs, neurons, and astrocytes [166]. In normal neurons, both SDF-1α and gp120 could stimulate phosphorylation of ERK1/2, while in NPCs and astrocytes, kinase activation is only induced by SDF-1α, but not gp120 [166]. In addition, SDF-1α also stimulates focal adhesion kinase (FAK) and Akt [34,164,165,167]. Although both ERK1/2 and Akt are coupled to CXCR4 in cerebellar granule neurons and neuroepithelioma cells, ERK1/2 activation shows a different dependency on the phosphatidyl inositol-3 kinase (PI3K) pathway, suggesting that different G proteins are involved in these two cell systems [165,168]. Furthermore, Floridi et al. [168] demonstrated that inhibition of either ERK or PI3K impedes the migration induced by SDF-1α in neuroepithelioma cells, while only PI3K is indispensable for the migration of cerebellar granule neuron. In normal astrocytes, G-protein-PI3K-ERK1/2 is regarded as the main signaling cascade linked to the SDF-1α-induced proliferation [169]. In addition, SDF-1α mediates tube-like structure formation of endothelial cells also through the PI3K pathway [32]. In embryonic hippocampal neurons, SDF-1α/CXCR4/G protein/ERK pathways stimulate production of glutamic acid decarboxylase-67 (GAD67) via Egr1 activation, which facilitates the maturation of GABAergic neurons [71].

SDF-1α/CXCR4 Axis and cAMP

The cyclic AMP (cAMP) signaling is critical for SDF-1α function in normal and malignant brain cells. Yang et al. [170] reported that SDF-1α-induced tumor growth relies on persistent suppression of cAMP. Pharmacologic elevation of cAMP inhibits growth of glioma cells in vitro and in vivo [170]. However, Odemis et al. [143] reported that dibutyryl cAMP enhances SDF-1α-induced chemotaxis in astroglia. They thought that factors positively coupled to cAMP may augment CXCR4 production and promote SDF-1α-induced chemotaxis [143].

Distribution of Tumor Cells with SDF-1α Methylation

Epigenetic mechanisms participate in the regulation of the expression of SDF-1α or CXCR4. One example is DNA methylation, a modification typically associated with inactivation of tumor suppressors. Methylation of SDF-1α is detected in 34.2% (26/76) of astrocytomas by methylation-specific PCR in our study [19], mainly in low-grade astrocytomas, via DNA hypermethylation by DNMT1, -3A, and -3B. However, it is interesting to note that 61.8% of tumors, mainly high-grade astrocytomas, display elevated SDF-1α mRNA, which suggests that SDF-1α promoter hypermethylation is an early event in astrocytoma development [19]. In addition, the CXCR4 promoter methylation with decreasing mRNA and protein levels was found in pancreatic cancer [171]. But study on CXCR4 promoter methylation in gliomas has not been performed. Further, histone modifications are also involved in the regulation of the expression of SDF-1α/CXCR4 in different cell types. Compared with brain microvascular pericytes, brain microvascular endothelial cells show an increase of histone H3 lysine 9 (H3K9) trimethylation and a decrease of H3K9 acetylation and H3K4 trimethylation [172].

Roles of the SDF-1α/CXCR4 Axis in Glioma

SDF-1α/CXCR4 Axis, Tumor Growth, and Cell Survival

SDF-1α/CXCR4 is required for proliferation of glioma cells. Exogenous SDF-1α induces proliferation of glioma cells in a dose-dependent manner [173]. SDF-1α regulates growth of glioma through an autocrine/paracrine mechanism. The blockage of CXCR4 induces neurite outgrowth, cellular differentiation, and a significant increase of apoptosis [20,174]. SDF-1α/CXCR4-induced cellular proliferation is correlated with phosphorylation and activation of ERK 1/2 and Akt, as discussed above.

As for neural progenitor cells, SDF-1α/CXCR4 mainly regulates not cell differentiation but cell motility, while overexpression of CXCR4 alone without SDF-1α inhibits cell proliferation [175]. Moreover, overexpression of CXCR4 in the presence of bFGF conversely suppresses cell proliferation, but further addition of SDF-1α to the NPCs reverses the cell proliferation back to control levels [175]. In addition, Khan et al. [176] found that SDF-1α supports survival and protects from apoptosis of postmitotic neurons through the counteraction of the Rb-E2F pathway. This finding suggests a neuronal protective role of the SDF-1α/CXCR4 signal in physiological or neurodegenerative and neuroinflammatory conditions [176].

SDF-1α/CXCR4 Axis and Tumor Migration

Migration is a hallmark of malignant gliomas and is the main reason for therapeutic failure and recurrence of the tumor [155]. The SDF-1α/CXCR4 axis is of great importance for cell migration. Rosenkranz et al. [177] reported that transplanted human umbilical cord blood cells with positive CXCR4 invade into the hypoxic-ischemic lesion of the rat brain within only 1 day. SDF-1α regulates the leading process of migration in glioma cells. Ehtesham et al. [178] found that invasive populations of glioma cells exhibited 25- to 89-fold higher expression of CXCR4 at the message and protein levels than noninvasive tumor cells did. In addition, neutralization of CXCR4 blocks the invasive ability of glioma cells [178]. SDF-1α-mediated glioma migration requires a long-term stimulation of intermediate conductance Ca2+-activated K+ channel (IK(Ca)) activity via ERK1/2, but not PI3K [163].

SDF-1α/CXCR4 Axis and Tumor Vasculogenesis/Angiogenesis

SDF-1α and CXCR4 are expressed in both glioma and endothelial cells, which could represent a possible prognostic factor [21,25,28,29]. The SDF-1α/CXCR4 signaling plays an important role in glioma vasculogenesis and angiogenesis, which is regarded as a cross talk between endothelial and tumor cells. Vasculogenesis and angiogenesis, although endothelial cells are involved in both of them, are supposed to play distinct roles in the etiology of primary and recurrent malignant gliomas [179,180]. Kenig et al. [181] reported that co-culturing of human GBM cells with HBMECs enhances tumor invasion and endothelial proliferation through the secretion of SDF-1α and SDF-1α-induced activity of MMP-9. Tumor vasculogenesis means homing and engraftment of bone marrow-derived vascular progenitors. SDF-1α, not VEGF, recruits vascular progenitors to mitotic neovasculature [180,182]. SDF-1α also influences their differentiated phenotypes. Hypoxia interacts with tumor-secreted SDF-1α to induce differentiation of vascular progenitor into pericytes and endothelium [182].

Imaging

Studies [22,183] demonstrated patients with gliomas of CXCR4 overexpression showed a statistically significant increase in the intensity and extent of peritumoral T2-weighted magnetic resonance imaging (MRI) signal abnormalities. Given the importance of the SDF-1α/CXCR4 signaling in the progress of glioma and poor prognosis of glioma, in the past years, a great deal of effort has been made to develop molecular imaging approaches to noninvasively evaluate SDF-1α or CXCR4 status. Specific SDF-1α or CXCR4 targeting imaging probes have been developed for multiple imaging modalities including single photon emission computed tomography (SPE/CT). Nimmagadda et al. [184] radiolabeled anti-CXCR4 monoclonal antibodies (125)I-12G5, which were used in experimental brain tumor xenografts of mice. Immunoimaging of CXCR4 expression was obtained by SPECT/CT, with a specific accumulation of (125)I-12G5 in U87 tumors. The tumor-to-muscle uptake ratios reached 15 +/- 3 at 48 h after injection [184]. Recombinant SDF-1α was radiolabeled using 99mTc-S-acetylmercaptoacetyltriserine-N-hydroxysuccinimide ([99mTc-MAS3]-NHS) [185]. However, this 99mTc-labeled SDF-1α radiotracer demonstrated no evidence of blood-brain barrier penetration.

SDF-1α/CXCR4 Axis and Radio-/Chemoresistance in Glioma

Despite the high doses of radiation delivered in the treatment of patients with glioma, the tumors invariably recur within the irradiation field [180]. Tabatabai et al. [131] demonstrated that irradiation induces tumor satellite formation at 21 days after intracerebral implantation of glioma. Irradiation enhances the tropism of bone marrow-derived cells (BMDCs) and HPCs to the gliomas, the proliferation of HPCs, and the vasculogenesis of BMDCs [131,180,186]. During these processes, SDF-1α has been identified as a key molecule. In glioma cells, SDF-1α promoter is activated at 24 h after irradiation at 8 Gy [131]. SDF-1α mediates the recruitment of HPCs to gliomas induced by irradiation via HIF-1α and TGF-β [131,187].

The SDF-1α/CXCR4 axis is also correlated with chemotherapeutic sensitivity of gliomas. Combination of AMD3100 with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) synergistically inhibits the proliferation of GBM cells [188]. SDF-1α was also identified as a predictor of the sensitivity of PDGF receptor inhibitor, named imatinib/Glivec/Gleevec/STI571 in high-grade gliomas [189]. SDF-1α can reverse the imatinib resistance of gliomas. These data suggest that molecule inhibitors of SDF-1α/CXCR4 interactions, in combination with conventional radiotherapy or chemotherapy, are a promising combinatorial strategy.

Inhibition and Clinical Trials

Plerixafor (AMD3100) is a bicyclam molecular that selectively and reversibly antagonizes the binding of CXCR4 to its ligand, which is approved by FDA to aid, in combination with granulocyte-colony stimulating factor (G-CSF), in stem cell mobilization for the treatment of multiple myeloma or non-Hodgkin lymphoma. AMD3100 is also employed in the treatment of gliomas, especially GBM, through multiple mechanisms. Firstly, AMD3100 inhibits growth of intracranial glioblastoma by increasing apoptosis and decreasing the proliferation of tumor cells [167]. Secondly, AMD3100 impedes the subpopulations of stem cells in GBM to infiltrate to the protective hypoxic niche [190]. Thirdly, AMD3100 blocks the function of SDF-1α, secreted by gliomas, by recruiting of NSCs to regions of brain tumor [43]. The combination between the antidepressant mirtazapine and the anti-fungal clotrimazole could block the intermediate conductance Ca2+-activated K+ channels, thereby inhibiting the SDF-1α/CXCR4 signaling synergistically with AMD3100 [190]. AMD3465 is the second generation of the CXCR4 small inhibitor. Monomacrocyclic AMD3465 behaves like its predecessor in blocking antibody binding to CXCR4 and in vivo tumor growth, with 10-fold more effectiveness than AMD3100 [170,191]. TC14012 is also developed as a peptidomimetic inverse agonist of CXCR4, recruiting β-arrestin to CXCR7 without detectable activation of G-proteins [192]. Cheng et al. [193] developed MAbs 6H7 and 7D4, two specific monoclonal antibodies against human CXCR4. Interestingly, MAb 6H7 enhances SDF-1α-induced proliferation in glioma cells, while MAb 7D4 blocks the function. Despite the difference in proliferation, both antibodies inhibit SDF-1α-induced chemotaxis of glioma cells.

Oncolytic virotherapy holds promise as a novel cancer treatment platform for gliomas. However, many barriers exist in clinical trials, including immune inactivation, mislocalization, specific and nonspecific sequestration, and inadequate distribution [194]. NSCs are highly migratory and could selectively recruit to areas of brain tumors, which might be exploited as delivery vehicles for gene therapy in gliomas [43,195,196,197]. Tyler et al. [196] infected NSCs with a conditionally replicating adenovirus CRAd-Survivin(S)-pk7, thereby successfully migrating and delivering CRAd to glioma. Sonabend et al. [198] effectively infected human mesenchymal stem cells (hMSC) with CRAd as well as a chimeric 5/3 fiber or RGD backbone through CXCR4 promoter driving E1A. Both CRAd-CXCR4-5/3 and CRAd-CXCR4-RGD-loaded hMSC selectively migrated and released CRAds to glioma [196].

Clinical Implications and Future Challenges

Since AMD3100 (plerixafor) is already approved for clinical use, the use of AMD3100 is regarded as most promising for further investigations in human clinical trials as a proof of principle [199]. In glioblastoma patients, SDF-1α/CXCR4 is responsible for restoring functional vasculature in irradiated tumors [199]. Furthermore, SDF-1α increases when tumors escape from anti-VEGF therapy [200]. This has clinical implications for the use of CXCR4 antagonists in combination with other targeted agents [201] as well as conventional radiotherapy or chemotherapy drugs. However, a number of challenges remain, including the efficacy for glioma patients, the appropriate stage of glioma to treat, the possibility of penetrating the blood-brain barrier, and possible adverse events in combination with other therapies. It is worth noting that CXCR7, another receptor for SDF-1α, is also essential for SDF-1α-stimulated glioma progression [202]. So, there is a great market potential to develop anti-SDF-1α monoclonal antibodies or antagonists that compete for both CXCR4 and CXCR7 receptors. Recently, Meincke et al. [203] synthesized fluorescent CXCL12-conjugates, which show a high sensitivity to detect primary and metastatic tumors by targeting tumor cells and tumor vasculature. However, this experiment showed no evidence of blood-brain barrier penetration. There is still a long way to go to find SDF-1α- or CXCR4-targeting imaging probes with high sensitivity and specificity for brain tumors.

Discussion

Increasing evidence supports that the SDF-1α/CXCR4 signaling plays a vital role in an enormous diversity of processes in both brain development and glioma progression, including migration, distribution, differentiation, proliferation, vasculogenesis/angiogenesis, and cellular functions. Gliomas are highly invasive and resistant to radiation and chemotherapy, and aberrant SDF-1α/CXCR4 signaling contributes to this resistance. Thus, the SDF-1α/CXCR4 signaling remains an attractive target for therapeutic intervention in glioma. However, a number of important questions remain unanswered. Firstly, how to press the switch of SDF-1α changing the SDF-1α/CXCR4 signaling from the endocrine loop to the autocrine and/or local paracrine loop in brain development and glioma progression. As CXCR4 is constitutively expressed in differentiated normal or tumor tissues, it is much more important to define possible mechanisms underlying the regulation of chemokine SDF-1α. Secondly, CXCR4 exhibits the highest mRNA levels at an early stage of brain development. CXCR4 expression tapers off soon during brain development. Another question that deserves further study is the controlling system or the upstream signal transduction of CXCR4 silence during brain development. Because many expressional and functional features of SDF-1α/CXCR4 signaling appear to be shared by brain development and glioma progression, studies in the field of brain development may provide valuable tactics for glioma treatment.

Acknowledgements

This work was supported by the National Natural Science Foundation of China, 30901536, and the Natural Science Foundation of Shandong, ZR2010HQ026. This study was also supported by the Promotive research fund for excellent young and middle-aged scientists of Shandong Province, BS2011SW015, and the Independent Innovation Foundation of Shandong University, 2010TS103.

Disclosure Statement

There are no financial or commercial conflicts of interest involved in this study.


References

  1. Gangadhar T, Nandi S, Salgia R: The role of chemokine receptor CXCR4 in lung cancer. Cancer Biol Ther 2010;9:409-416.
  2. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50-56.
  3. Scala S, Giuliano P, Ascierto PA, Ieranò C, Franco R, Napolitano M, Ottaiano A, Lombardi ML, Luongo M, Simeone E, Castiglia D, Mauro F, De Michele I, Calemma R, Botti G, Caracò C, Nicoletti G, Satriano RA, Castello G: Human melanoma metastases express functional CXCR4. Clin Cancer Res 2006;12:2427-2433.
  4. Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB: Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene 2006;25:4986-4997.
  5. Otsuka S, Bebb G: The CXCR4/SDF-1 chemokine receptor axis: a new target therapeutic for non-small cell lung cancer. J Thorac Oncol 2008;3:1379-1383.
  6. Drury LJ, Ziarek JJ, Gravel S, Veldkamp CT, Takekoshi T, Hwang ST, Heveker N, Volkman BF, Dwinell MB: Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. Proc Natl Acad Sci USA 2011;108:17655-17660.
  7. Janowski M: Functional diversity of SDF-1 splicing variants. Cell Adh Migr 2009;3:243-249.
  8. Banisadr G, Skrzydelski D, Kitabgi P, Rostène W, Parsadaniantz SM: Highly regionalized distribution of stromal cell-derived factor-1/CXCL12 in adult rat brain: constitutive expression in cholinergic, dopaminergic and vasopressinergic neurons. Eur J Neurosci 2003;18:1593-1606.
  9. Banisadr G, Dicou E, Berbar T, Rostène W, Lombet A, Haour F: Characterization and visualization of [125I] stromal cell-derived factor-1alpha binding to CXCR4 receptors in rat brain and human neuroblastoma cells. J Neuroimmunol 2000;110:151-160.
  10. Banisadr G, Fontanges P, Haour F, Kitabgi P, Rostène W, Mélik Parsadaniantz S: Neuroanatomical distribution of CXCR4 in adult rat brain and its localization in cholinergic and dopaminergic neurons. Eur J Neurosci 2002;16:1661-1671.
  11. Trecki J, Brailoiu GC, Unterwald EM: Localization of CXCR4 in the forebrain of the adult rat. Brain Res 2010;1315:53-62.
  12. Westmoreland SV, Alvarez X, deBakker C, Aye P, Wilson ML, Williams KC, Lackner AA: Developmental expression patterns of CCR5 and CXCR4 in the rhesus macaque brain. J Neuroimmunol 2002;122:146-158.
  13. van der Meer P, Ulrich AM, Gonźalez-Scarano F, Lavi E: Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. Exp Mol Pathol 2000;69:192-201.
  14. Köller H, Schaal H, Rosenbaum C, Czardybon M, Von Giesen HJ, Müller HW, Arendt G: Functional CXCR4 receptor development parallels sensitivity to HIV-1 gp120 in cultured rat astroglial cells but not in cultured rat cortical neurons. J Neurovirol 2002;8:411-419.
  15. Van Der Meer P, Goldberg SH, Fung KM, Sharer LR, González-Scarano F, Lavi E: Expression pattern of CXCR3, CXCR4, and CCR3 chemokine receptors in the developing human brain. J Neuropathol Exp Neurol 2001;60:25-32.
    External Resources
  16. Futahashi Y, Komano J, Urano E, Aoki T, Hamatake M, Miyauchi K, Yoshida T, Koyanagi Y, Matsuda Z, Yamamoto N: Separate elements are required for ligand-dependent and -independent internalization of metastatic potentiator CXCR4. Cancer Sci 2007;98:373-379.
  17. Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F: The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem 2005,21;280:35760-35766.
  18. Schönemeier B, Kolodziej A, Schulz S, Jacobs S, Hoellt V, Stumm R: Regional and cellular localization of the CXCl12/SDF-1 chemokine receptor CXCR7 in the developing and adult rat brain. J Comp Neurol 2008;510:207-220.
  19. Zhou W, Jiang Z, Song X, Liu Y, Wen P, Guo Y, Xu F, Kong L, Zhang P, Han A, Yu J: Promoter hypermethylation-mediated down-regulation of CXCL12 in human astrocytoma. J Neurosci Res 2008;86:3002-3010.
  20. Sehgal A, Keener C, Boynton AL, Warrick J, Murphy GP: CXCR-4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells. J Surg Oncol 1998;69:99-104.
  21. Rempel SA, Dudas S, Ge S, Gutiérrez JA: Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 2000;6:102-111.
    External Resources
  22. Stevenson CB, Ehtesham M, McMillan KM, Valadez JG, Edgeworth ML, Price RR, Abel TW, Mapara KY, Thompson RC: CXCR4 expression is elevated in glioblastoma multiforme and correlates with an increase in intensity and extent of peritumoral T2-weighted magnetic resonance imaging signal abnormalities. Neurosurgery 2008;63:560-569; discussion 569-570.
  23. Yang SX, Chen JH, Jiang XF, Wang QL, Chen ZQ, Zhao W, Feng YH, Xin R, Shi JQ, Bian XW: Activation of chemokine receptor CXCR4 in malignant glioma cells promotes the production of vascular endothelial growth factor. Biochem Biophys Res Commun 2005;335:523-528.
  24. Woerner BM, Warrington NM, Kung AL, Perry A, Rubin JB: Widespread CXCR4 activation in astrocytomas revealed by phospho-CXCR4-specific antibodies. Cancer Res 2005;65:11392-11399.
  25. Bian XW, Yang SX, Chen JH, Ping YF, Zhou XD, Wang QL, Jiang XF, Gong W, Xiao HL, Du LL, Chen ZQ, Zhao W, Shi JQ, Wang JM: Preferential expression of chemokine receptor CXCR4 by highly malignant human gliomas and its association with poor patient survival. Neurosurgery 2007;61:570-578; discussion 578-579.
  26. Barbero S, Bajetto A, Bonavia R, Porcile C, Piccioli P, Pirani P, Ravetti JL, Zona G, Spaziante R, Florio T, Schettini G: Expression of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1 in human brain tumors and their involvement in glial proliferation in vitro. Ann NY Acad Sci 2002;973:60-69.
  27. Komatani H, Sugita Y, Arakawa F, Ohshima K, Shigemori M: Expression of CXCL12 on pseudopalisading cells and proliferating microvessels in glioblastomas: an accelerated growth factor in glioblastomas. Int J Oncol 2009;34:665-672.
  28. Salmaggi A, Gelati M, Pollo B, Marras C, Silvani A, Balestrini MR, Eoli M, Fariselli L, Broggi G, Boiardi A: CXCL12 expression is predictive of a shorter time to tumor progression in low-grade glioma: a single-institution study in 50 patients. J Neurooncol 2005;74:287-293.
  29. Maderna E, Salmaggi A, Calatozzolo C, Limido L, Pollo B: Nestin, PDGFRbeta, CXCL12 and VEGF in glioma patients: different profiles of (pro-angiogenic) molecule expression are related with tumor grade and may provide prognostic information. Cancer Biol Ther 2007;6:1018-1024.
  30. Calatozzolo C, Maderna E, Pollo B, Gelati M, Marras C, Silvani A, Croci D, Boiardi A, Salmaggi A: Prognostic value of CXCL12 expression in 40 low-grade oligodendrogliomas and oligoastrocytomas. Cancer Biol Ther 2006;5:827-832.
  31. McCandless EE, Wang Q, Woerner BM, Harper JM, Klein RS: CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J Immunol 2006;177:8053-8064.
    External Resources
  32. Kanda S, Mochizuki Y, Kanetake H: Stromal cell-derived factor-1alpha induces tube-like structure formation of endothelial cells through phosphoinositide 3-kinase. J Biol Chem 2003;278:257-262.
  33. Bajetto A, Barbieri F, Dorcaratto A, Barbero S, Daga A, Porcile C, Ravetti JL, Zona G, Spaziante R, Corte G, Schettini G, Florio T: Expression of CXC chemokine receptors 1-5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int 2006;49:423-432.
  34. Zagzag D, Esencay M, Mendez O, Yee H, Smirnova I, Huang Y, Chiriboga L, Lukyanov E, Liu M, Newcomb EW: Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer's structures. Am J Pathol 2008;173:545-560.
  35. Zhou W, Jiang Z, Liu N, Xu F, Wen P, Liu Y, Zhong W, Song X, Chang X, Zhang X, Wei G, Yu J: Down-regulation of CXCL12 mRNA expression by promoter hypermethylation and its association with metastatic progression in human breast carcinomas. J Cancer Res Clin Oncol 2009;135:91-102.
  36. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50-56.
  37. Wendt MK, Cooper AN, Dwinell MB: Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene 2008;27:1461-1471.
  38. Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti JL, Zona GL, Spaziante R, Florio T, Schettini G: Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 2003;63:1969-1974.
    External Resources
  39. Sutton A, Friand V, Brulé-Donneger S, Chaigneau T, Ziol M, Sainte-Catherine O, Poiré A, Saffar L, Kraemer M, Vassy J, Nahon P, Salzmann JL, Gattegno L, Charnaux N: Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res 2007;5:21-33.
  40. Gonzalez-Perez O, Jauregui-Huerta F, Galvez-Contreras AY: Immune system modulates the function of adult neural stem cells. Curr Immunol Rev 2010;6:167-173.
  41. Pritchett J, Wright C, Zeef L, Nadarajah B: Stromal derived factor-1 exerts differential regulation on distinct cortical cell populations in vitro. BMC Dev Biol 2007;7:31.
  42. Tissir F, Wang CE, Goffinet AM: Expression of the chemokine receptor Cxcr4 mRNA during mouse brain development. Brain Res Dev Brain Res 2004;149:63-71.
  43. van der Meulen AA, Biber K, Lukovac S, Balasubramaniyan V, den Dunnen WF, Boddeke HW, Mooij JJ: The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour. Neuropathol Appl Neurobiol 2009;35:579-591.
  44. Peng H, Huang Y, Rose J, Erichsen D, Herek S, Fujii N, Tamamura H, Zheng J: Stromal cell-derived factor 1-mediated CXCR4 signaling in rat and human cortical neural progenitor cells. J Neurosci Res 2004;76:35-50.
  45. Krathwohl MD, Kaiser JL: Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 2004;22:109-118.
  46. Li M, Chang CJ, Lathia JD, Wang L, Pacenta HL, Cotleur A, Ransohoff RM: Chemokine receptor CXCR4 signaling modulates the growth factor-induced cell cycle of self-renewing and multipotent neural progenitor cells. Glia 2011;59:108-118.
  47. Li M, Ransohoff RM: Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol 2008;84:116-131.
  48. Borrell V, Marín O: Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling. Nat Neurosci 2006;9:1284-1293.
  49. Paredes MF, Li G, Berger O, Baraban SC, Pleasure SJ: Stromal-derived factor-1 (CXCL12) regulates laminar position of Cajal-Retzius cells in normal and dysplastic brains. J Neurosci 2006;26:9404-9412.
  50. Stumm RK, Zhou C, Ara T, Lazarini F, Dubois-Dalcq M, Nagasawa T, Höllt V, Schulz S: CXCR4 regulates interneuron migration in the developing neocortex. J Neurosci 2003;23:5123-5130.
    External Resources
  51. Marchionni I, Takács VT, Nunzi MG, Mugnaini E, Miller RJ, Maccaferri G: Distinctive properties of CXC chemokine receptor 4-expressing Cajal-Retzius cells versus GABAergic interneurons of the postnatal hippocampus. J Physiol 2010;588:2859-2878.
  52. Zhu Y, Yu T, Zhang XC, Nagasawa T, Wu JY, Rao Y: Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci 2002;5:719-720.
  53. Yu T, Huang H, Li HF: Stromal cell-derived factor-1 promotes migration of cells from the upper rhombic lip in cerebellar development. J Neurosci Res 2010;88:2775-2786.
  54. Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA, Luster AD: SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development 2001;128:1971-1981.
    External Resources
  55. Bagri A, Gurney T, He X, Zou YR, Littman DR, Tessier-Lavigne M, Pleasure SJ: The chemokine SDF1 regulates migration of dentate granule cells. Development 2002;129:4249-4260.
    External Resources
  56. Li G, Kataoka H, Coughlin SR, Pleasure SJ: Identification of a transient subpial neurogenic zone in the developing dentate gyrus and its regulation by Cxcl12 and reelin signaling. Development 2009;136:327-335.
  57. Lu M, Grove EA, Miller RJ: Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci USA 2002;99:7090-7095.
  58. Ohshima Y, Kubo T, Koyama R, Ueno M, Nakagawa M, Yamashita T: Regulation of axonal elongation and pathfinding from the entorhinal cortex to the dentate gyrus in the hippocampus by the chemokine stromal cell-derived factor 1 alpha. J Neurosci 2008;28:8344-8353.
  59. Berger O, Li G, Han SM, Paredes M, Pleasure SJ: Expression of SDF-1 and CXCR4 during reorganization of the postnatal dentate gyrus. Dev Neurosci 2007;29:48-58.
  60. Bhattacharyya BJ, Banisadr G, Jung H, Ren D, Cronshaw DG, Zou Y, Miller RJ: The chemokine stromal cell-derived factor-1 regulates GABAergic inputs to neural progenitors in the postnatal dentate gyrus. J Neurosci 2008;28:6720-6730.
  61. López-Bendito G, Sánchez-Alcañiz JA, Pla R, Borrell V, Picó E, Valdeolmillos M, Marín O: Chemokine signaling controls intracortical migration and final distribution of GABAergic interneurons. J Neurosci 2008;28:1613-1624.
  62. Anderson SA, Kaznowski CE, Horn C, Rubenstein JL, McConnell SK: Distinct origins of neocortical projection neurons and interneurons in vivo. Cereb Cortex 2002;12:702-709.
  63. Letinic K, Zoncu R, Rakic P: Origin of GABAergic neurons in the human neocortex. Nature 2002;417:645-649.
  64. Tiveron MC, Rossel M, Moepps B, Zhang YL, Seidenfaden R, Favor J, König N, Cremer H: Molecular interaction between projection neuron precursors and invading interneurons via stromal-derived factor 1 (CXCL12)/CXCR4 signaling in the cortical subventricular zone/intermediate zone. J Neurosci 2006;26:13273-13278.
  65. Khan MZ, Brandimarti R, Musser BJ, Resue DM, Fatatis A, Meucci O: The chemokine receptor CXCR4 regulates cell-cycle proteins in neurons. J Neurovirol 2003;9:300-314.
  66. Tanaka DH, Mikami S, Nagasawa T, Miyazaki J, Nakajima K, Murakami F: CXCR4 is required for proper regional and laminar distribution of cortical somatostatin-, calretinin-, and neuropeptide Y-expressing GABAergic interneurons. Cereb Cortex 2010;20:2810-2817.
  67. Liodis P, Denaxa M, Grigoriou M, Akufo-Addo C, Yanagawa Y, Pachnis V: Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes. J Neurosci 2007;27:3078-3089.
  68. Li G, Adesnik H, Li J, Long J, Nicoll RA, Rubenstein JL, Pleasure SJ: Regional distribution of cortical interneurons and development of inhibitory tone are regulated by Cxcl12/Cxcr4 signaling. J Neurosci 2008;28:1085-1098.
  69. Stumm R, Kolodziej A, Schulz S, Kohtz JD, Höllt V: Patterns of SDF-1alpha and SDF-1gamma mRNAs, migration pathways, and phenotypes of CXCR4-expressing neurons in the developing rat telencephalon. J Comp Neurol 2007;502:382-399.
  70. Liapi A, Pritchett J, Jones O, Fujii N, Parnavelas JG, Nadarajah B: Stromal-derived factor 1 signalling regulates radial and tangential migration in the developing cerebral cortex. Dev Neurosci 2008;30:117-131.
  71. Luo Y, Lathia J, Mughal M, Mattson MP: SDF1alpha/CXCR4 signaling, via ERKs and the transcription factor Egr1, induces expression of a 67-kDa form of glutamic acid decarboxylase in embryonic hippocampal neurons. J Biol Chem 2008;283:24789-24800.
  72. Arakawa Y, Bito H, Furuyashiki T, Tsuji T, Takemoto-Kimura S, Kimura K, Nozaki K, Hashimoto N, Narumiya S: Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons. J Cell Biol 2003;161:381-391.
  73. Pujol F, Kitabgi P, Boudin H: The chemokine SDF-1 differentially regulates axonal elongation and branching in hippocampal neurons. J Cell Sci 2005;118:1071-1080.
  74. Xiang Y, Li Y, Zhang Z, Cui K, Wang S, Yuan XB, Wu CP, Poo MM, Duan S: Nerve growth cone guidance mediated by G protein-coupled receptors. Nat Neurosci 2002;5:843-848.
  75. Baudouin SJ, Pujol F, Nicot A, Kitabgi P, Boudin H: Dendrite-selective redistribution of the chemokine receptor CXCR4 following agonist stimulation. Mol Cell Neurosci 2006;33:160-169.
  76. Miyasaka N, Knaut H, Yoshihara Y: Cxcl12/Cxcr4 chemokine signaling is required for placode assembly and sensory axon pathfinding in the zebrafish olfactory system. Development 2007;134:2459-2468.
  77. Limatola C, Giovannelli A, Maggi L, Ragozzino D, Castellani L, Ciotti MT, Vacca F, Mercanti D, Santoni A, Eusebi F: SDF-1alpha-mediated modulation of synaptic transmission in rat cerebellum. Eur J Neurosci 2000;12:2497-2504.
  78. Ragozzino D, Renzi M, Giovannelli A, Eusebi F: Stimulation of chemokine CXC receptor 4 induces synaptic depression of evoked parallel fibers inputs onto Purkinje neurons in mouse cerebellum. J Neuroimmunol 2002;127:30-36.
  79. Guyon A, Rovère C, Cervantes A, Allaeys I, Nahon JL: Stromal cell-derived factor-1alpha directly modulates voltage-dependent currents of the action potential in mammalian neuronal cells. J Neurochem 2005;93:963-973.
  80. Liu Z, Geng L, Li R, He X, Zheng JQ, Xie Z: Frequency modulation of synchronized Ca2+ spikes in cultured hippocampal networks through G-protein-coupled receptors. J Neurosci 2003;23:4156-4163.
    External Resources
  81. Mohajerani MH, Cherubini E: Role of giant depolarizing potentials in shaping synaptic currents in the developing hippocampus. Crit Rev Neurobiol 2006;18:13-23.
  82. Kasiyanov A, Fujii N, Tamamura H, Xiong H: Modulation of network-driven, GABA-mediated giant depolarizing potentials by SDF-1alpha in the developing hippocampus. Dev Neurosci 2008;30:285-292.
  83. Kolodziej A, Schulz S, Guyon A, Wu DF, Pfeiffer M, Odemis V, Höllt V, Stumm R: Tonic activation of CXC chemokine receptor 4 in immature granule cells supports neurogenesis in the adult dentate gyrus. J Neurosci 2008;28:4488-4500.
  84. Zhu Y, Matsumoto T, Mikami S, Nagasawa T, Murakami F: SDF1/CXCR4 signalling regulates two distinct processes of precerebellar neuronal migration and its depletion leads to abnormal pontine nuclei formation. Development 2009;136:1919-1928.
  85. Dziembowska M, Tham TN, Lau P, Vitry S, Lazarini F, Dubois-Dalcq M: A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia 2005;50:258-269.
  86. Kadi L, Selvaraju R, de Lys P, Proudfoot AE, Wells TN, Boschert U: Differential effects of chemokines on oligodendrocyte precursor proliferation and myelin formation in vitro. J Neuroimmunol 2006;174:133-146.
  87. Patel JR, McCandless EE, Dorsey D, Klein RS: CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. Proc Natl Acad Sci USA 2010;107:11062-11067.
  88. Calì C, Bezzi P: CXCR4-mediated glutamate exocytosis from astrocytes. J Neuroimmunol 2010;224:13-21.
  89. Prebil M, Jensen J, Zorec R, Kreft M: Astrocytes and energy metabolism. Arch Physiol Biochem 2011;117:64-69.
  90. Barbieri F, Bajetto A, Porcile C, Pattarozzi A, Schettini G, Florio T: Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior pituitary function. J Mol Endocrinol 2007;38:383-389.
  91. Florio T, Casagrande S, Diana F, Bajetto A, Porcile C, Zona G, Thellung S, Arena S, Pattarozzi A, Corsaro A, Spaziante R, Robello M, Schettini G: Chemokine stromal cell-derived factor 1alpha induces proliferation and growth hormone release in GH4C1 rat pituitary adenoma cell line through multiple intracellular signals. Mol Pharmacol 2006;69:539-546.
  92. Lee Y, Kim JM, Lee EJ: Functional expression of CXCR4 in somatotrophs: CXCL12 activates GH gene, GH production and secretion, and cellular proliferation. J Endocrinol 2008;199:191-199.
  93. Palevitch O, Abraham E, Borodovsky N, Levkowitz G, Zohar Y, Gothilf Y: Cxcl12a-Cxcr4b signaling is important for proper development of the forebrain GnRH system in zebrafish. Gen Comp Endocrinol 2010;165:262-268.
  94. Schwarting GA, Henion TR, Nugent JD, Caplan B, Tobet S: Stromal cell-derived factor-1 (chemokine C-X-C motif ligand 12) and chemokine C-X-C motif receptor 4 are required for migration of gonadotropin-releasing hormone neurons to the forebrain. J Neurosci 2006;26:6834-6840.
  95. Toba Y, Tiong JD, Ma Q, Wray S: CXCR4/SDF-1 system modulates development of GnRH-1 neurons and the olfactory system. Dev Neurobiol 2008;68:487-503.
  96. Guyon A, Banisadr G, Rovère C, Cervantes A, Kitabgi P, Melik-Parsadaniantz S, Nahon JL: Complex effects of stromal cell-derived factor-1 alpha on melanin-concentrating hormone neuron excitability. Eur J Neurosci 2005;21:701-710.
  97. Callewaere C, Banisadr G, Desarménien MG, Mechighel P, Kitabgi P, Rostène WH, Mélik Parsadaniantz S: The chemokine SDF-1/CXCL12 modulates the firing pattern of vasopressin neurons and counteracts induced vasopressin release through CXCR4. Proc Natl Acad Sci USA 2006;103:8221-8226.
  98. Callewaere C, Fernette B, Raison D, Mechighel P, Burlet A, Calas A, Kitabgi P, Parsadaniantz SM, Rostène W: Cellular and subcellular evidence for neuronal interaction between the chemokine stromal cell-derived factor-1/CXCL 12 and vasopressin: regulation in the hypothalamo-neurohypophysial system of the Brattleboro rats. Endocrinology 2008;149:310-319.
  99. Shimoji M, Pagan F, Healton EB, Mocchetti I: CXCR4 and CXCL12 expression is increased in the nigro-striatal system of Parkinson's disease. Neurotox Res 2009;16:318-328.
  100. Skrzydelski D, Guyon A, Daugé V, Rovère C, Apartis E, Kitabgi P, Nahon JL, Rostène W, Parsadaniantz SM: The chemokine stromal cell-derived factor-1/CXCL12 activates the nigrostriatal dopamine system. J Neurochem 2007;102:1175-1183.
  101. Guyon A, Skrzydelski D, Rovère C, Apartis E, Rostène W, Kitabgi P, Mélik Parsadaniantz S, Nahon JL: Stromal-cell-derived factor 1alpha /CXCL12 modulates high-threshold calcium currents in rat substantia nigra. Eur J Neurosci 2008;28:862-870.
  102. Guyon A, Skrzydelsi D, Rovère C, Rostène W, Parsadaniantz SM, Nahon JL: Stromal cell-derived factor-1alpha modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms. J Neurochem 2006;96:1540-1550.
  103. Wang F, Yasuhara T, Shingo T, Kameda M, Tajiri N, Yuan WJ, Kondo A, Kadota T, Baba T, Tayra JT, Kikuchi Y, Miyoshi Y, Date I: Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha. BMC Neurosci 2010;11:52.
  104. Heinisch S, Palma J, Kirby LG: Interactions between chemokine and mu-opioid receptors: anatomical findings and electrophysiological studies in the rat periaqueductal grey. Brain Behav Immun 2011;25:360-372.
  105. Pello OM, Martínez-Muñoz L, Parrillas V, Serrano A, Rodríguez-Frade JM, Toro MJ, Lucas P, Monterrubio M, Martínez-A C, Mellado M: Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur J Immunol 2008;38:537-549.
  106. Burbassi S, Aloyo VJ, Simansky KJ, Meucci O: GTPgammaS incorporation in the rat brain: a study on mu-opioid receptors and CXCR4. J Neuroimmune Pharmacol 2008;3:26-34.
  107. Finley MJ, Chen X, Bardi G, Davey P, Geller EB, Zhang L, Adler MW, Rogers TJ: Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the kappa-opioid receptor. J Neuroimmunol 2008;197:114-123.
  108. Benamar K, Palma J, Cowan A, Geller EB, Adler MW: Analgesic efficacy of buprenorphine in the presence of high levels of SDF-1α/CXCL12 in the brain. Drug Alcohol Depend 2011;114:246-248.
  109. Szabo I, Chen XH, Xin L, Adler MW, Howard OM, Oppenheim JJ, Rogers TJ: Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. Proc Natl Acad Sci USA 2002;99:10276-10281.
  110. Burbassi S, Sengupta R, Meucci O: Alterations of CXCR4 function in µ-opioid receptor-deficient glia. Eur J Neurosci 2010;32:1278-1288.
  111. Adler MW, Rogers TJ: Are chemokines the third major system in the brain? J Leukoc Biol 2005;78:1204-1209.
  112. Benamar K, Geller EB, Adler MW: First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain. J Pharmacol Exp Ther 2008;325:641-645.
  113. Benamar K, Yondorf M, Geller EB, Eisenstein TK, Adler MW: Physiological evidence for interaction between the HIV-1 co-receptor CXCR4 and the cannabinoid system in the brain. Br J Pharmacol 2009;157:1225-1231.
  114. Heinisch S, Kirby LG: SDF-1alpha/CXCL12 enhances GABA and glutamate synaptic activity at serotonin neurons in the rat dorsal raphe nucleus. Neuropharmacology 2010;58:501-514.
  115. Hermann GE, Van Meter MJ, Rogers RC: CXCR4 receptors in the dorsal medulla: implications for autonomic dysfunction. Eur J Neurosci 2008;27:855-864.
  116. Lieberam I, Agalliu D, Nagasawa T, Ericson J, Jessell TM: A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 2005;47:667-679.
  117. Odemis V, Lamp E, Pezeshki G, Moepps B, Schilling K, Gierschik P, Littman DR, Engele J: Mice deficient in the chemokine receptor CXCR4 exhibit impaired limb innervation and myogenesis. Mol Cell Neurosci 2005;30:494-505.
  118. Parachikova A, Cotman CW: Reduced CXCL12/CXCR4 results in impaired learning and is downregulated in a mouse model of Alzheimer disease. Neurobiol Dis 2007;28:143-153.
  119. Parachikova A, Nichol KE, Cotman CW: Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol Dis 2008;30:121-129.
  120. Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, Höllt V, Schulz S: A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci 2002;22:5865-5878.
    External Resources
  121. Hill WD, Hess DC, Martin-Studdard A, Carothers JJ, Zheng J, Hale D, Maeda M, Fagan SC, Carroll JE, Conway SJ: SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol 2004;63:84-96.
    External Resources
  122. Robin AM, Zhang ZG, Wang L, Zhang RL, Katakowski M, Zhang L, Wang Y, Zhang C, Chopp M: Stromal cell-derived factor 1alpha mediates neural progenitor cell motility after focal cerebral ischemia. J Cereb Blood Flow Metab 2006;26:125-134.
  123. Chang YC, Shyu WC, Lin SZ, Li H: Regenerative therapy for stroke. Cell Transplant 2007;16:171-181.
    External Resources
  124. Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB, Newcomb EW: Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 2006;86:1221-1232.
  125. Salcedo R, Oppenheim JJ: Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 2003;10:359-370.
  126. Mirshahi F, Pourtau J, Li H, Muraine M, Trochon V, Legrand E, Vannier J, Soria J, Vasse M, Soria C: SDF-1 activity on microvascular endothelial cells: consequences on angiogenesis in in vitro and in vivo models. Thromb Res 2000;99:587-594.
  127. Salcedo R, Resau JH, Halverson D, Hudson EA, Dambach M, Powell D, Wasserman K, Oppenheim JJ: Differential expression and responsiveness of chemokine receptors (CXCR1-3) by human microvascular endothelial cells and umbilical vein endothelial cells. FASEB J 2000;14:2055-2064.
  128. Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, Kleinman HK, Murphy WJ, Oppenheim JJ: Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol 1999;154:1125-1135.
  129. Hong X, Jiang F, Kalkanis SN, Zhang ZG, Zhang XP, DeCarvalho AC, Katakowski M, Bobbitt K, Mikkelsen T, Chopp M: SDF-1 and CXCR4 are up-regulated by VEGF and contribute to glioma cell invasion. Cancer Lett 2006;236:39-45.
  130. Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, Melamed J, Semenza GL: Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res 2005;65:6178-6188.
  131. Tabatabai G, Frank B, Möhle R, Weller M, Wick W: Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-beta-dependent HIF-1alpha-mediated induction of CXCL12. Brain 2006;129:2426-2435.
  132. Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB, Pollack IF, Park DM: Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 2009;28:3949-3959.
  133. Zhao D, Najbauer J, Garcia E, Metz MZ, Gutova M, Glackin CA, Kim SU, Aboody KS: Neural stem cell tropism to glioma: critical role of tumor hypoxia. Mol Cancer Res 2008;6:1819-1829.
  134. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A: CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 2001;4:702-710.
  135. Calì C, Marchaland J, Regazzi R, Bezzi P: SDF 1-alpha (CXCL12) triggers glutamate exocytosis from astrocytes on a millisecond time scale: imaging analysis at the single-vesicle level with TIRF microscopy. J Neuroimmunol 2008;198:82-91.
  136. Oh JW, Drabik K, Kutsch O, Choi C, Tousson A, Benveniste EN: CXC chemokine receptor 4 expression and function in human astroglioma cells. J Immunol 2001;166:2695-2704.
    External Resources
  137. Croitoru-Lamoury J, Guillemin GJ, Boussin FD, Mognetti B, Gigout LI, Chéret A, Vaslin B, Le Grand R, Brew BJ, Dormont D: Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation. Glia 2003;41:354-370.
  138. Salcedo R, Oppenheim JJ: Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 2003;10:359-370.
  139. Egea V, von Baumgarten L, Schichor C, Berninger B, Popp T, Neth P, Goldbrunner R, Kienast Y, Winkler F, Jochum M, Ries C: TNF-α respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma. Cell Death Differ 2011;18:853-863.
  140. Han Y, Wang J, He T, Ransohoff RM: TNF-alpha down-regulates CXCR4 expression in primary murine astrocytes. Brain Res 2001;888:1-10.
  141. Salmaggi A, Gelati M, Pollo B, Frigerio S, Eoli M, Silvani A, Broggi G, Ciusani E, Croci D, Boiardi A, De Rossi M: CXCL12 in malignant glial tumors: a possible role in angiogenesis and cross-talk between endothelial and tumoral cells. J Neurooncol 2004;67:305-317.
  142. McCandless EE, Budde M, Lees JR, Dorsey D, Lyng E, Klein RS: IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. J Immunol 2009;183:613-620.
  143. Odemis V, Moepps B, Gierschik P, Engele J: Interleukin-6 and cAMP induce stromal cell-derived factor-1 chemotaxis in astroglia by up-regulating CXCR4 cell surface expression. Implications for brain inflammation. J Biol Chem 2002;277:39801-39808.
  144. Ping YF, Yao XH, Bian XW, Chen JH, Zhang R, Yi L, Zhou ZH: Activation of CXCR4 in human glioma stem cells promotes tumor angiogenesis. Zhonghua Bing Li Xue Za Zhi 2007;36:179-183.
    External Resources
  145. Ping YF, Yao XH, Chen JH, Liu H, Chen DL, Zhou XD, Wang JM, Bian XW: The anti-cancer compound Nordy inhibits CXCR4-mediated production of IL-8 and VEGF by malignant human glioma cells. J Neurooncol 2007;84:21-29.
  146. Boos L, Szalai AJ, Barnum SR: C3a expressed in the central nervous system protects against LPS-induced shock. Neurosci Lett 2005;387:68-71.
  147. Shinjyo N, Ståhlberg A, Dragunow M, Pekny M, Pekna M: Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells 2009;27:2824-2832.
  148. Zhang J, Sarkar S, Yong VW: The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. Carcinogenesis 2005;26:2069-2077.
  149. Wu M, Chen Q, Li D, Li X, Li X, Huang C, Tang Y, Zhou Y, Wang D, Tang K, Cao L, Shen S, Li G: LRRC4 inhibits human glioblastoma cells proliferation, invasion, and proMMP-2 activation by reducing SDF-1 alpha/CXCR4-mediated ERK1/2 and Akt signaling pathways. J Cell Biochem 2008;103:245-255.
  150. Stremenova J, Krepela E, Mares V, Trim J, Dbaly V, Marek J, Vanickova Z, Lisa V, Yea C, Sedo A: Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade. Int J Oncol 2007;31:785-792.
    External Resources
  151. Christopherson KW 2nd, Hangoc G, Broxmeyer HE: Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol 2002;169:7000-7008.
    External Resources
  152. Busek P, Stremenová J, Krepela E, Sedo A: Modulation of substance P signaling by dipeptidyl peptidase-IV enzymatic activity in human glioma cell lines. Physiol Res 2008;57:443-449.
    External Resources
  153. Nosheny RL, Ahmed F, Yakovlev A, Meyer EM, Ren K, Tessarollo L, Mocchetti I: Brain-derived neurotrophic factor prevents the nigrostriatal degeneration induced by human immunodeficiency virus-1 glycoprotein 120 in vivo. Eur J Neurosci 2007;25:2275-2284.
  154. Ahmed F, Tessarollo L, Thiele C, Mocchetti I: Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain. Brain Res 2008;1227:1-11.
  155. Esencay M, Newcomb EW, Zagzag D: HGF upregulates CXCR4 expression in gliomas via NF-kappaB: implications for glioma cell migration. J Neurooncol 2010;99:33-40.
  156. Tu H, Zhou Z, Liang Q, Li Z, Li D, Qing J, Wang H, Zhang L: CXCR4 and SDF-1 production are stimulated by hepatocyte growth factor and promote glioma cell invasion. Onkologie 2009;32:331-336.
  157. Cook A, Hippensteel R, Shimizu S, Nicolai J, Fatatis A, Meucci O: Interactions between chemokines: regulation of fractalkine/CX3CL1 homeostasis by SDF/CXCL12 in cortical neurons. J Biol Chem 2010;285:10563-10571.
  158. Alvarez S, Blanco A, Fresno M, Muñoz-Fernández MA: Nuclear factor-kappaB activation regulates cyclooxygenase-2 induction in human astrocytes in response to CXCL12: role in neuronal toxicity. J Neurochem 2010;113:772-783.
  159. Alvarez S, Serramía MJ, Fresno M, Muñoz-Fernández MA: HIV-1 envelope glycoprotein 120 induces cyclooxygenase-2 expression in astrocytoma cells through a nuclear factor-kappaB-dependent mechanism. Neuromolecular Med 2007;9:179-193.
  160. Hagihara K, Zhang EE, Ke YH, Liu G, Liu JJ, Rao Y, Feng GS: Shp2 acts downstream of SDF-1alpha/CXCR4 in guiding granule cell migration during cerebellar development. Dev Biol 2009;334:276-284.
  161. Oh JW, Olman M, Benveniste EN: CXCL12-mediated induction of plasminogen activator inhibitor-1 expression in human CXCR4 positive astroglioma cells. Biol Pharm Bull 2009;32:573-577.
  162. Williams CK, Segarra M, Sierra Mde L, Sainson RC, Tosato G, Harris AL: Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells. Cancer Res 2008;68:1889-1895.
  163. Sciaccaluga M, Fioretti B, Catacuzzeno L, Pagani F, Bertollini C, Rosito M, Catalano M, D'Alessandro G, Santoro A, Cantore G, Ragozzino D, Castigli E, Franciolini F, Limatola C: CXCL12-induced glioblastoma cell migration requires intermediate conductance Ca2+-activated K+ channel activity. Am J Physiol Cell Physiol 2010;299:C175-C184.
  164. Zhou Y, Larsen PH, Hao C, Yong VW: CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem 2002;277:49481-49487.
  165. Bajetto A, Barbero S, Bonavia R, Piccioli P, Pirani P, Florio T, Schettini G: Stromal cell-derived factor-1alpha induces astrocyte proliferation through the activation of extracellular signal-regulated kinases 1/2 pathway. J Neurochem 2001;77:1226-1236.
  166. Lazarini F, Casanova P, Tham TN, De Clercq E, Arenzana-Seisdedos F, Baleux F, Dubois-Dalcq M: Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes. Eur J Neurosci 2000;12:117-125.
  167. Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, Kieran MW, Luster AD, Segal RA: A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 2003;100:13513-13518.
  168. Floridi F, Trettel F, Di Bartolomeo S, Ciotti MT, Limatola C: Signalling pathways involved in the chemotactic activity of CXCL12 in cultured rat cerebellar neurons and CHP100 neuroepithelioma cells. J Neuroimmunol 2003;135:38-46.
  169. Bonavia R, Bajetto A, Barbero S, Pirani P, Florio T, Schettini G: Chemokines and their receptors in the CNS: expression of CXCL12/SDF-1 and CXCR4 and their role in astrocyte proliferation. Toxicol Lett 2003;139:181-189.
  170. Yang L, Jackson E, Woerner BM, Perry A, Piwnica-Worms D, Rubin JB: Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res 2007;67:651-658.
  171. Sato N, Matsubayashi H, Fukushima N, Goggins M: The chemokine receptor CXCR4 is regulated byDNA methylation in pancreatic cancer. Cancer Biol Ther 2005;4:70-76.
  172. Seo J, Kim YO, Jo I: Differential expression of stromal cell-derived factor 1 in human brain microvascular endothelial cells and pericytes involves histone modifications. Biochem Biophys Res Commun 2009;382:519-524.
  173. Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti JL, Zona GL, Spaziante R, Florio T, Schettini G: Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 2003;63:1969-1974.
    External Resources
  174. do Carmo A, Patricio I, Cruz MT, Carvalheiro H, Oliveira CR, Lopes MC: CXCL12/CXCR4 promotes motility and proliferation of glioma cells. Cancer Biol Ther 2010;9:56-65.
  175. Liu XS, Chopp M, Santra M, Hozeska-Solgot A, Zhang RL, Wang L, Teng H, Lu M, Zhang ZG: Functional response to SDF1 alpha through over-expression of CXCR4 on adult subventricular zone progenitor cells. Brain Res 2008;1226:18-26.
  176. Khan MZ, Brandimarti R, Shimizu S, Nicolai J, Crowe E, Meucci O: The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein. Cell Death Differ 2008;15:1663-1672.
  177. Rosenkranz K, Kumbruch S, Lebermann K, Marschner K, Jensen A, Dermietzel R, Meier C: The chemokine SDF-1/CXCL12 contributes to the ‘homing' of umbilical cord blood cells to a hypoxic-ischemic lesion in the rat brain. J Neurosci Res 2010;88:1223-1233.
  178. Ehtesham M, Winston JA, Kabos P, Thompson RC: CXCR4 expression mediates glioma cell invasiveness. Oncogene 2006;25:2801-2806.
  179. Greenfield JP, Cobb WS, Lyden D: Resisting arrest: a switch from angiogenesis to vasculogenesis in recurrent malignant gliomas. J Clin Invest 2010;120:663-667.
  180. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM: Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 2010;120:694-705.
  181. Kenig S, Alonso MB, Mueller MM, Lah TT: Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9. Cancer Lett 2010;289:53-61.
  182. Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA: Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res 2006;66:9054-9064.
  183. McMillan KM, Ehtesham M, Stevenson CB, Edgeworth ML, Thompson RC, Price RR: T2 detection of tumor invasion within segmented components of glioblastoma multiforme. J Magn Reson Imaging 2009;29:251-257.
  184. Nimmagadda S, Pullambhatla M, Pomper MG: Immunoimaging of CXCR4 expression in brain tumor xenografts using SPECT/CT. J Nucl Med 2009;50:1124-1130.
  185. Misra P, Lebeche D, Ly H, Schwarzkopf M, Diaz G, Hajjar RJ, Schecter AD, Frangioni JV: Quantitation of CXCR4 expression in myocardial infarction using 99mTc-labeled SDF-1alpha. J Nucl Med 2008;49:963-969.
  186. Park SA, Ryu CH, Kim SM, Lim JY, Park SI, Jeong CH, Jun JA, Oh JH, Park SH, Oh W, Jeun SS: CXCR4-transfected human umbilical cord blood-derived mesenchymal stem cells exhibit enhanced migratory capacity toward gliomas. Int J Oncol 2011;38:97-103.
  187. Tabatabai G, Bähr O, Möhle R, Eyüpoglu IY, Boehmler AM, Wischhusen J, Rieger J, Blümcke I, Weller M, Wick W: Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells. Brain 2005;128:2200-2211.
  188. Redjal N, Chan JA, Segal RA, Kung AL: CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas. Clin Cancer Res 2006;12:6765-6771.
  189. Hägerstrand D, Hesselager G, Achterberg S, Wickenberg Bolin U, Kowanetz M, Kastemar M, Heldin CH, Isaksson A, Nistér M, Ostman A: Characterization of an imatinib-sensitive subset of high-grade human glioma cultures. Oncogene 2006;25:4913-4922.
  190. Kast RE: Profound blockage of CXCR4 signaling at multiple points using the synergy between plerixafor, mirtazapine, and clotrimazole as a new glioblastoma treatment adjunct. Turk Neurosurg 2010;20:425-429.
  191. Hatse S, Princen K, De Clercq E, Rosenkilde MM, Schwartz TW, Hernandez-Abad PE, Skerlj RT, Bridger GJ, Schols D: AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor. Biochem Pharmacol 2005;70:752-761.
  192. Gravel S, Malouf C, Boulais PE, Berchiche YA, Oishi S, Fujii N, Leduc R, Sinnett D, Heveker N: The peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: roles of receptor domains. J Biol Chem 2010;285:37939-37943.
  193. Cheng Z, Zhou S, Wang X, Xie F, Wu H, Liu G, Wang Q, Chen Y, Hu Y, Lu B, Zhang X: Characterization and application of two novel monoclonal antibodies against human CXCR4: cell proliferation and migration regulation for glioma cell line in vitro by CXCR4/SDF-1alpha signal. Hybridoma (Larchmt) 2009;28:33-41.
  194. Kottke T, Hall G, Pulido J, Diaz RM, Thompson J, Chong H, Selby P, Coffey M, Pandha H, Chester J, Melcher A, Harrington K, Vile R: Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice. J Clin Invest 2010;120:1551-1560.
  195. Müller FJ, Snyder EY, Loring JF: Gene therapy: can neural stem cells deliver? Nat Rev Neurosci 2006;7:75-84.
  196. Tyler MA, Ulasov IV, Sonabend AM, Nandi S, Han Y, Marler S, Roth J, Lesniak MS: Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo. Gene Ther 2009;16:262-278.
  197. Ehtesham M, Yuan X, Kabos P, Chung NH, Liu G, Akasaki Y, Black KL, Yu JS: Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 2004;6:287-293.
    External Resources
  198. Sonabend AM, Ulasov IV, Tyler MA, Rivera AA, Mathis JM, Lesniak MS: Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells 2008;26:831-841.
  199. Tseng D, Vasquez-Medrano DA, Brown JM: Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas. Br J Cancer 2011;104:1805-1809.
  200. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95.
  201. Wong D, Korz W: Translating an antagonist of chemokine receptor CXCR4: from bench to bedside. Clin Cancer Res 2008;14:7975-7980.
  202. Hattermann K, Mentlein R, Held-Feindt J: CXCL12 mediates apoptosis resistance in rat C6 glioma cells. Oncol Rep 2012;27:1348-1352.
  203. Meincke M, Tiwari S, Hattermann K, Kalthoff H, Mentlein R: Near-infrared molecular imaging of tumors via chemokine receptors CXCR4 and CXCR7. Clin Exp Metastasis 2011;28:713-720.

Author Contacts

Yemin Liang

Department of Radiotherapy, Cancer Centre

Qilu Hospital, Shandong University, 107 Wenhuaxi Street

Jinan, Shandong Province 250012 (PR China)

Tel. +86 531 8216 9821, E-Mail dryeminliang@yahoo.cn


Article / Publication Details

First-Page Preview
Abstract of Review

Received: January 26, 2012
Accepted: April 24, 2012
Published online: August 21, 2012
Issue release date: May 2013

Number of Print Pages: 19
Number of Figures: 3
Number of Tables: 0

ISSN: 1424-862X (Print)
eISSN: 1424-8638 (Online)

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References

  1. Gangadhar T, Nandi S, Salgia R: The role of chemokine receptor CXCR4 in lung cancer. Cancer Biol Ther 2010;9:409-416.
  2. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50-56.
  3. Scala S, Giuliano P, Ascierto PA, Ieranò C, Franco R, Napolitano M, Ottaiano A, Lombardi ML, Luongo M, Simeone E, Castiglia D, Mauro F, De Michele I, Calemma R, Botti G, Caracò C, Nicoletti G, Satriano RA, Castello G: Human melanoma metastases express functional CXCR4. Clin Cancer Res 2006;12:2427-2433.
  4. Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB: Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene 2006;25:4986-4997.
  5. Otsuka S, Bebb G: The CXCR4/SDF-1 chemokine receptor axis: a new target therapeutic for non-small cell lung cancer. J Thorac Oncol 2008;3:1379-1383.
  6. Drury LJ, Ziarek JJ, Gravel S, Veldkamp CT, Takekoshi T, Hwang ST, Heveker N, Volkman BF, Dwinell MB: Monomeric and dimeric CXCL12 inhibit metastasis through distinct CXCR4 interactions and signaling pathways. Proc Natl Acad Sci USA 2011;108:17655-17660.
  7. Janowski M: Functional diversity of SDF-1 splicing variants. Cell Adh Migr 2009;3:243-249.
  8. Banisadr G, Skrzydelski D, Kitabgi P, Rostène W, Parsadaniantz SM: Highly regionalized distribution of stromal cell-derived factor-1/CXCL12 in adult rat brain: constitutive expression in cholinergic, dopaminergic and vasopressinergic neurons. Eur J Neurosci 2003;18:1593-1606.
  9. Banisadr G, Dicou E, Berbar T, Rostène W, Lombet A, Haour F: Characterization and visualization of [125I] stromal cell-derived factor-1alpha binding to CXCR4 receptors in rat brain and human neuroblastoma cells. J Neuroimmunol 2000;110:151-160.
  10. Banisadr G, Fontanges P, Haour F, Kitabgi P, Rostène W, Mélik Parsadaniantz S: Neuroanatomical distribution of CXCR4 in adult rat brain and its localization in cholinergic and dopaminergic neurons. Eur J Neurosci 2002;16:1661-1671.
  11. Trecki J, Brailoiu GC, Unterwald EM: Localization of CXCR4 in the forebrain of the adult rat. Brain Res 2010;1315:53-62.
  12. Westmoreland SV, Alvarez X, deBakker C, Aye P, Wilson ML, Williams KC, Lackner AA: Developmental expression patterns of CCR5 and CXCR4 in the rhesus macaque brain. J Neuroimmunol 2002;122:146-158.
  13. van der Meer P, Ulrich AM, Gonźalez-Scarano F, Lavi E: Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia. Exp Mol Pathol 2000;69:192-201.
  14. Köller H, Schaal H, Rosenbaum C, Czardybon M, Von Giesen HJ, Müller HW, Arendt G: Functional CXCR4 receptor development parallels sensitivity to HIV-1 gp120 in cultured rat astroglial cells but not in cultured rat cortical neurons. J Neurovirol 2002;8:411-419.
  15. Van Der Meer P, Goldberg SH, Fung KM, Sharer LR, González-Scarano F, Lavi E: Expression pattern of CXCR3, CXCR4, and CCR3 chemokine receptors in the developing human brain. J Neuropathol Exp Neurol 2001;60:25-32.
    External Resources
  16. Futahashi Y, Komano J, Urano E, Aoki T, Hamatake M, Miyauchi K, Yoshida T, Koyanagi Y, Matsuda Z, Yamamoto N: Separate elements are required for ligand-dependent and -independent internalization of metastatic potentiator CXCR4. Cancer Sci 2007;98:373-379.
  17. Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F: The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. J Biol Chem 2005,21;280:35760-35766.
  18. Schönemeier B, Kolodziej A, Schulz S, Jacobs S, Hoellt V, Stumm R: Regional and cellular localization of the CXCl12/SDF-1 chemokine receptor CXCR7 in the developing and adult rat brain. J Comp Neurol 2008;510:207-220.
  19. Zhou W, Jiang Z, Song X, Liu Y, Wen P, Guo Y, Xu F, Kong L, Zhang P, Han A, Yu J: Promoter hypermethylation-mediated down-regulation of CXCL12 in human astrocytoma. J Neurosci Res 2008;86:3002-3010.
  20. Sehgal A, Keener C, Boynton AL, Warrick J, Murphy GP: CXCR-4, a chemokine receptor, is overexpressed in and required for proliferation of glioblastoma tumor cells. J Surg Oncol 1998;69:99-104.
  21. Rempel SA, Dudas S, Ge S, Gutiérrez JA: Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma. Clin Cancer Res 2000;6:102-111.
    External Resources
  22. Stevenson CB, Ehtesham M, McMillan KM, Valadez JG, Edgeworth ML, Price RR, Abel TW, Mapara KY, Thompson RC: CXCR4 expression is elevated in glioblastoma multiforme and correlates with an increase in intensity and extent of peritumoral T2-weighted magnetic resonance imaging signal abnormalities. Neurosurgery 2008;63:560-569; discussion 569-570.
  23. Yang SX, Chen JH, Jiang XF, Wang QL, Chen ZQ, Zhao W, Feng YH, Xin R, Shi JQ, Bian XW: Activation of chemokine receptor CXCR4 in malignant glioma cells promotes the production of vascular endothelial growth factor. Biochem Biophys Res Commun 2005;335:523-528.
  24. Woerner BM, Warrington NM, Kung AL, Perry A, Rubin JB: Widespread CXCR4 activation in astrocytomas revealed by phospho-CXCR4-specific antibodies. Cancer Res 2005;65:11392-11399.
  25. Bian XW, Yang SX, Chen JH, Ping YF, Zhou XD, Wang QL, Jiang XF, Gong W, Xiao HL, Du LL, Chen ZQ, Zhao W, Shi JQ, Wang JM: Preferential expression of chemokine receptor CXCR4 by highly malignant human gliomas and its association with poor patient survival. Neurosurgery 2007;61:570-578; discussion 578-579.
  26. Barbero S, Bajetto A, Bonavia R, Porcile C, Piccioli P, Pirani P, Ravetti JL, Zona G, Spaziante R, Florio T, Schettini G: Expression of the chemokine receptor CXCR4 and its ligand stromal cell-derived factor 1 in human brain tumors and their involvement in glial proliferation in vitro. Ann NY Acad Sci 2002;973:60-69.
  27. Komatani H, Sugita Y, Arakawa F, Ohshima K, Shigemori M: Expression of CXCL12 on pseudopalisading cells and proliferating microvessels in glioblastomas: an accelerated growth factor in glioblastomas. Int J Oncol 2009;34:665-672.
  28. Salmaggi A, Gelati M, Pollo B, Marras C, Silvani A, Balestrini MR, Eoli M, Fariselli L, Broggi G, Boiardi A: CXCL12 expression is predictive of a shorter time to tumor progression in low-grade glioma: a single-institution study in 50 patients. J Neurooncol 2005;74:287-293.
  29. Maderna E, Salmaggi A, Calatozzolo C, Limido L, Pollo B: Nestin, PDGFRbeta, CXCL12 and VEGF in glioma patients: different profiles of (pro-angiogenic) molecule expression are related with tumor grade and may provide prognostic information. Cancer Biol Ther 2007;6:1018-1024.
  30. Calatozzolo C, Maderna E, Pollo B, Gelati M, Marras C, Silvani A, Croci D, Boiardi A, Salmaggi A: Prognostic value of CXCL12 expression in 40 low-grade oligodendrogliomas and oligoastrocytomas. Cancer Biol Ther 2006;5:827-832.
  31. McCandless EE, Wang Q, Woerner BM, Harper JM, Klein RS: CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J Immunol 2006;177:8053-8064.
    External Resources
  32. Kanda S, Mochizuki Y, Kanetake H: Stromal cell-derived factor-1alpha induces tube-like structure formation of endothelial cells through phosphoinositide 3-kinase. J Biol Chem 2003;278:257-262.
  33. Bajetto A, Barbieri F, Dorcaratto A, Barbero S, Daga A, Porcile C, Ravetti JL, Zona G, Spaziante R, Corte G, Schettini G, Florio T: Expression of CXC chemokine receptors 1-5 and their ligands in human glioma tissues: role of CXCR4 and SDF1 in glioma cell proliferation and migration. Neurochem Int 2006;49:423-432.
  34. Zagzag D, Esencay M, Mendez O, Yee H, Smirnova I, Huang Y, Chiriboga L, Lukyanov E, Liu M, Newcomb EW: Hypoxia- and vascular endothelial growth factor-induced stromal cell-derived factor-1alpha/CXCR4 expression in glioblastomas: one plausible explanation of Scherer's structures. Am J Pathol 2008;173:545-560.
  35. Zhou W, Jiang Z, Liu N, Xu F, Wen P, Liu Y, Zhong W, Song X, Chang X, Zhang X, Wei G, Yu J: Down-regulation of CXCL12 mRNA expression by promoter hypermethylation and its association with metastatic progression in human breast carcinomas. J Cancer Res Clin Oncol 2009;135:91-102.
  36. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature 2001;410:50-56.
  37. Wendt MK, Cooper AN, Dwinell MB: Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells. Oncogene 2008;27:1461-1471.
  38. Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti JL, Zona GL, Spaziante R, Florio T, Schettini G: Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 2003;63:1969-1974.
    External Resources
  39. Sutton A, Friand V, Brulé-Donneger S, Chaigneau T, Ziol M, Sainte-Catherine O, Poiré A, Saffar L, Kraemer M, Vassy J, Nahon P, Salzmann JL, Gattegno L, Charnaux N: Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res 2007;5:21-33.
  40. Gonzalez-Perez O, Jauregui-Huerta F, Galvez-Contreras AY: Immune system modulates the function of adult neural stem cells. Curr Immunol Rev 2010;6:167-173.
  41. Pritchett J, Wright C, Zeef L, Nadarajah B: Stromal derived factor-1 exerts differential regulation on distinct cortical cell populations in vitro. BMC Dev Biol 2007;7:31.
  42. Tissir F, Wang CE, Goffinet AM: Expression of the chemokine receptor Cxcr4 mRNA during mouse brain development. Brain Res Dev Brain Res 2004;149:63-71.
  43. van der Meulen AA, Biber K, Lukovac S, Balasubramaniyan V, den Dunnen WF, Boddeke HW, Mooij JJ: The role of CXC chemokine ligand (CXCL)12-CXC chemokine receptor (CXCR)4 signalling in the migration of neural stem cells towards a brain tumour. Neuropathol Appl Neurobiol 2009;35:579-591.
  44. Peng H, Huang Y, Rose J, Erichsen D, Herek S, Fujii N, Tamamura H, Zheng J: Stromal cell-derived factor 1-mediated CXCR4 signaling in rat and human cortical neural progenitor cells. J Neurosci Res 2004;76:35-50.
  45. Krathwohl MD, Kaiser JL: Chemokines promote quiescence and survival of human neural progenitor cells. Stem Cells 2004;22:109-118.
  46. Li M, Chang CJ, Lathia JD, Wang L, Pacenta HL, Cotleur A, Ransohoff RM: Chemokine receptor CXCR4 signaling modulates the growth factor-induced cell cycle of self-renewing and multipotent neural progenitor cells. Glia 2011;59:108-118.
  47. Li M, Ransohoff RM: Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology. Prog Neurobiol 2008;84:116-131.
  48. Borrell V, Marín O: Meninges control tangential migration of hem-derived Cajal-Retzius cells via CXCL12/CXCR4 signaling. Nat Neurosci 2006;9:1284-1293.
  49. Paredes MF, Li G, Berger O, Baraban SC, Pleasure SJ: Stromal-derived factor-1 (CXCL12) regulates laminar position of Cajal-Retzius cells in normal and dysplastic brains. J Neurosci 2006;26:9404-9412.
  50. Stumm RK, Zhou C, Ara T, Lazarini F, Dubois-Dalcq M, Nagasawa T, Höllt V, Schulz S: CXCR4 regulates interneuron migration in the developing neocortex. J Neurosci 2003;23:5123-5130.
    External Resources
  51. Marchionni I, Takács VT, Nunzi MG, Mugnaini E, Miller RJ, Maccaferri G: Distinctive properties of CXC chemokine receptor 4-expressing Cajal-Retzius cells versus GABAergic interneurons of the postnatal hippocampus. J Physiol 2010;588:2859-2878.
  52. Zhu Y, Yu T, Zhang XC, Nagasawa T, Wu JY, Rao Y: Role of the chemokine SDF-1 as the meningeal attractant for embryonic cerebellar neurons. Nat Neurosci 2002;5:719-720.
  53. Yu T, Huang H, Li HF: Stromal cell-derived factor-1 promotes migration of cells from the upper rhombic lip in cerebellar development. J Neurosci Res 2010;88:2775-2786.
  54. Klein RS, Rubin JB, Gibson HD, DeHaan EN, Alvarez-Hernandez X, Segal RA, Luster AD: SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development 2001;128:1971-1981.
    External Resources
  55. Bagri A, Gurney T, He X, Zou YR, Littman DR, Tessier-Lavigne M, Pleasure SJ: The chemokine SDF1 regulates migration of dentate granule cells. Development 2002;129:4249-4260.
    External Resources
  56. Li G, Kataoka H, Coughlin SR, Pleasure SJ: Identification of a transient subpial neurogenic zone in the developing dentate gyrus and its regulation by Cxcl12 and reelin signaling. Development 2009;136:327-335.
  57. Lu M, Grove EA, Miller RJ: Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci USA 2002;99:7090-7095.
  58. Ohshima Y, Kubo T, Koyama R, Ueno M, Nakagawa M, Yamashita T: Regulation of axonal elongation and pathfinding from the entorhinal cortex to the dentate gyrus in the hippocampus by the chemokine stromal cell-derived factor 1 alpha. J Neurosci 2008;28:8344-8353.
  59. Berger O, Li G, Han SM, Paredes M, Pleasure SJ: Expression of SDF-1 and CXCR4 during reorganization of the postnatal dentate gyrus. Dev Neurosci 2007;29:48-58.
  60. Bhattacharyya BJ, Banisadr G, Jung H, Ren D, Cronshaw DG, Zou Y, Miller RJ: The chemokine stromal cell-derived factor-1 regulates GABAergic inputs to neural progenitors in the postnatal dentate gyrus. J Neurosci 2008;28:6720-6730.
  61. López-Bendito G, Sánchez-Alcañiz JA, Pla R, Borrell V, Picó E, Valdeolmillos M, Marín O: Chemokine signaling controls intracortical migration and final distribution of GABAergic interneurons. J Neurosci 2008;28:1613-1624.
  62. Anderson SA, Kaznowski CE, Horn C, Rubenstein JL, McConnell SK: Distinct origins of neocortical projection neurons and interneurons in vivo. Cereb Cortex 2002;12:702-709.
  63. Letinic K, Zoncu R, Rakic P: Origin of GABAergic neurons in the human neocortex. Nature 2002;417:645-649.
  64. Tiveron MC, Rossel M, Moepps B, Zhang YL, Seidenfaden R, Favor J, König N, Cremer H: Molecular interaction between projection neuron precursors and invading interneurons via stromal-derived factor 1 (CXCL12)/CXCR4 signaling in the cortical subventricular zone/intermediate zone. J Neurosci 2006;26:13273-13278.
  65. Khan MZ, Brandimarti R, Musser BJ, Resue DM, Fatatis A, Meucci O: The chemokine receptor CXCR4 regulates cell-cycle proteins in neurons. J Neurovirol 2003;9:300-314.
  66. Tanaka DH, Mikami S, Nagasawa T, Miyazaki J, Nakajima K, Murakami F: CXCR4 is required for proper regional and laminar distribution of cortical somatostatin-, calretinin-, and neuropeptide Y-expressing GABAergic interneurons. Cereb Cortex 2010;20:2810-2817.
  67. Liodis P, Denaxa M, Grigoriou M, Akufo-Addo C, Yanagawa Y, Pachnis V: Lhx6 activity is required for the normal migration and specification of cortical interneuron subtypes. J Neurosci 2007;27:3078-3089.
  68. Li G, Adesnik H, Li J, Long J, Nicoll RA, Rubenstein JL, Pleasure SJ: Regional distribution of cortical interneurons and development of inhibitory tone are regulated by Cxcl12/Cxcr4 signaling. J Neurosci 2008;28:1085-1098.
  69. Stumm R, Kolodziej A, Schulz S, Kohtz JD, Höllt V: Patterns of SDF-1alpha and SDF-1gamma mRNAs, migration pathways, and phenotypes of CXCR4-expressing neurons in the developing rat telencephalon. J Comp Neurol 2007;502:382-399.
  70. Liapi A, Pritchett J, Jones O, Fujii N, Parnavelas JG, Nadarajah B: Stromal-derived factor 1 signalling regulates radial and tangential migration in the developing cerebral cortex. Dev Neurosci 2008;30:117-131.
  71. Luo Y, Lathia J, Mughal M, Mattson MP: SDF1alpha/CXCR4 signaling, via ERKs and the transcription factor Egr1, induces expression of a 67-kDa form of glutamic acid decarboxylase in embryonic hippocampal neurons. J Biol Chem 2008;283:24789-24800.
  72. Arakawa Y, Bito H, Furuyashiki T, Tsuji T, Takemoto-Kimura S, Kimura K, Nozaki K, Hashimoto N, Narumiya S: Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons. J Cell Biol 2003;161:381-391.
  73. Pujol F, Kitabgi P, Boudin H: The chemokine SDF-1 differentially regulates axonal elongation and branching in hippocampal neurons. J Cell Sci 2005;118:1071-1080.
  74. Xiang Y, Li Y, Zhang Z, Cui K, Wang S, Yuan XB, Wu CP, Poo MM, Duan S: Nerve growth cone guidance mediated by G protein-coupled receptors. Nat Neurosci 2002;5:843-848.
  75. Baudouin SJ, Pujol F, Nicot A, Kitabgi P, Boudin H: Dendrite-selective redistribution of the chemokine receptor CXCR4 following agonist stimulation. Mol Cell Neurosci 2006;33:160-169.
  76. Miyasaka N, Knaut H, Yoshihara Y: Cxcl12/Cxcr4 chemokine signaling is required for placode assembly and sensory axon pathfinding in the zebrafish olfactory system. Development 2007;134:2459-2468.
  77. Limatola C, Giovannelli A, Maggi L, Ragozzino D, Castellani L, Ciotti MT, Vacca F, Mercanti D, Santoni A, Eusebi F: SDF-1alpha-mediated modulation of synaptic transmission in rat cerebellum. Eur J Neurosci 2000;12:2497-2504.
  78. Ragozzino D, Renzi M, Giovannelli A, Eusebi F: Stimulation of chemokine CXC receptor 4 induces synaptic depression of evoked parallel fibers inputs onto Purkinje neurons in mouse cerebellum. J Neuroimmunol 2002;127:30-36.
  79. Guyon A, Rovère C, Cervantes A, Allaeys I, Nahon JL: Stromal cell-derived factor-1alpha directly modulates voltage-dependent currents of the action potential in mammalian neuronal cells. J Neurochem 2005;93:963-973.
  80. Liu Z, Geng L, Li R, He X, Zheng JQ, Xie Z: Frequency modulation of synchronized Ca2+ spikes in cultured hippocampal networks through G-protein-coupled receptors. J Neurosci 2003;23:4156-4163.
    External Resources
  81. Mohajerani MH, Cherubini E: Role of giant depolarizing potentials in shaping synaptic currents in the developing hippocampus. Crit Rev Neurobiol 2006;18:13-23.
  82. Kasiyanov A, Fujii N, Tamamura H, Xiong H: Modulation of network-driven, GABA-mediated giant depolarizing potentials by SDF-1alpha in the developing hippocampus. Dev Neurosci 2008;30:285-292.
  83. Kolodziej A, Schulz S, Guyon A, Wu DF, Pfeiffer M, Odemis V, Höllt V, Stumm R: Tonic activation of CXC chemokine receptor 4 in immature granule cells supports neurogenesis in the adult dentate gyrus. J Neurosci 2008;28:4488-4500.
  84. Zhu Y, Matsumoto T, Mikami S, Nagasawa T, Murakami F: SDF1/CXCR4 signalling regulates two distinct processes of precerebellar neuronal migration and its depletion leads to abnormal pontine nuclei formation. Development 2009;136:1919-1928.
  85. Dziembowska M, Tham TN, Lau P, Vitry S, Lazarini F, Dubois-Dalcq M: A role for CXCR4 signaling in survival and migration of neural and oligodendrocyte precursors. Glia 2005;50:258-269.
  86. Kadi L, Selvaraju R, de Lys P, Proudfoot AE, Wells TN, Boschert U: Differential effects of chemokines on oligodendrocyte precursor proliferation and myelin formation in vitro. J Neuroimmunol 2006;174:133-146.
  87. Patel JR, McCandless EE, Dorsey D, Klein RS: CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination. Proc Natl Acad Sci USA 2010;107:11062-11067.
  88. Calì C, Bezzi P: CXCR4-mediated glutamate exocytosis from astrocytes. J Neuroimmunol 2010;224:13-21.
  89. Prebil M, Jensen J, Zorec R, Kreft M: Astrocytes and energy metabolism. Arch Physiol Biochem 2011;117:64-69.
  90. Barbieri F, Bajetto A, Porcile C, Pattarozzi A, Schettini G, Florio T: Role of stromal cell-derived factor 1 (SDF1/CXCL12) in regulating anterior pituitary function. J Mol Endocrinol 2007;38:383-389.
  91. Florio T, Casagrande S, Diana F, Bajetto A, Porcile C, Zona G, Thellung S, Arena S, Pattarozzi A, Corsaro A, Spaziante R, Robello M, Schettini G: Chemokine stromal cell-derived factor 1alpha induces proliferation and growth hormone release in GH4C1 rat pituitary adenoma cell line through multiple intracellular signals. Mol Pharmacol 2006;69:539-546.
  92. Lee Y, Kim JM, Lee EJ: Functional expression of CXCR4 in somatotrophs: CXCL12 activates GH gene, GH production and secretion, and cellular proliferation. J Endocrinol 2008;199:191-199.
  93. Palevitch O, Abraham E, Borodovsky N, Levkowitz G, Zohar Y, Gothilf Y: Cxcl12a-Cxcr4b signaling is important for proper development of the forebrain GnRH system in zebrafish. Gen Comp Endocrinol 2010;165:262-268.
  94. Schwarting GA, Henion TR, Nugent JD, Caplan B, Tobet S: Stromal cell-derived factor-1 (chemokine C-X-C motif ligand 12) and chemokine C-X-C motif receptor 4 are required for migration of gonadotropin-releasing hormone neurons to the forebrain. J Neurosci 2006;26:6834-6840.
  95. Toba Y, Tiong JD, Ma Q, Wray S: CXCR4/SDF-1 system modulates development of GnRH-1 neurons and the olfactory system. Dev Neurobiol 2008;68:487-503.
  96. Guyon A, Banisadr G, Rovère C, Cervantes A, Kitabgi P, Melik-Parsadaniantz S, Nahon JL: Complex effects of stromal cell-derived factor-1 alpha on melanin-concentrating hormone neuron excitability. Eur J Neurosci 2005;21:701-710.
  97. Callewaere C, Banisadr G, Desarménien MG, Mechighel P, Kitabgi P, Rostène WH, Mélik Parsadaniantz S: The chemokine SDF-1/CXCL12 modulates the firing pattern of vasopressin neurons and counteracts induced vasopressin release through CXCR4. Proc Natl Acad Sci USA 2006;103:8221-8226.
  98. Callewaere C, Fernette B, Raison D, Mechighel P, Burlet A, Calas A, Kitabgi P, Parsadaniantz SM, Rostène W: Cellular and subcellular evidence for neuronal interaction between the chemokine stromal cell-derived factor-1/CXCL 12 and vasopressin: regulation in the hypothalamo-neurohypophysial system of the Brattleboro rats. Endocrinology 2008;149:310-319.
  99. Shimoji M, Pagan F, Healton EB, Mocchetti I: CXCR4 and CXCL12 expression is increased in the nigro-striatal system of Parkinson's disease. Neurotox Res 2009;16:318-328.
  100. Skrzydelski D, Guyon A, Daugé V, Rovère C, Apartis E, Kitabgi P, Nahon JL, Rostène W, Parsadaniantz SM: The chemokine stromal cell-derived factor-1/CXCL12 activates the nigrostriatal dopamine system. J Neurochem 2007;102:1175-1183.
  101. Guyon A, Skrzydelski D, Rovère C, Apartis E, Rostène W, Kitabgi P, Mélik Parsadaniantz S, Nahon JL: Stromal-cell-derived factor 1alpha /CXCL12 modulates high-threshold calcium currents in rat substantia nigra. Eur J Neurosci 2008;28:862-870.
  102. Guyon A, Skrzydelsi D, Rovère C, Rostène W, Parsadaniantz SM, Nahon JL: Stromal cell-derived factor-1alpha modulation of the excitability of rat substantia nigra dopaminergic neurones: presynaptic mechanisms. J Neurochem 2006;96:1540-1550.
  103. Wang F, Yasuhara T, Shingo T, Kameda M, Tajiri N, Yuan WJ, Kondo A, Kadota T, Baba T, Tayra JT, Kikuchi Y, Miyoshi Y, Date I: Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1alpha. BMC Neurosci 2010;11:52.
  104. Heinisch S, Palma J, Kirby LG: Interactions between chemokine and mu-opioid receptors: anatomical findings and electrophysiological studies in the rat periaqueductal grey. Brain Behav Immun 2011;25:360-372.
  105. Pello OM, Martínez-Muñoz L, Parrillas V, Serrano A, Rodríguez-Frade JM, Toro MJ, Lucas P, Monterrubio M, Martínez-A C, Mellado M: Ligand stabilization of CXCR4/delta-opioid receptor heterodimers reveals a mechanism for immune response regulation. Eur J Immunol 2008;38:537-549.
  106. Burbassi S, Aloyo VJ, Simansky KJ, Meucci O: GTPgammaS incorporation in the rat brain: a study on mu-opioid receptors and CXCR4. J Neuroimmune Pharmacol 2008;3:26-34.
  107. Finley MJ, Chen X, Bardi G, Davey P, Geller EB, Zhang L, Adler MW, Rogers TJ: Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the kappa-opioid receptor. J Neuroimmunol 2008;197:114-123.
  108. Benamar K, Palma J, Cowan A, Geller EB, Adler MW: Analgesic efficacy of buprenorphine in the presence of high levels of SDF-1α/CXCL12 in the brain. Drug Alcohol Depend 2011;114:246-248.
  109. Szabo I, Chen XH, Xin L, Adler MW, Howard OM, Oppenheim JJ, Rogers TJ: Heterologous desensitization of opioid receptors by chemokines inhibits chemotaxis and enhances the perception of pain. Proc Natl Acad Sci USA 2002;99:10276-10281.
  110. Burbassi S, Sengupta R, Meucci O: Alterations of CXCR4 function in µ-opioid receptor-deficient glia. Eur J Neurosci 2010;32:1278-1288.
  111. Adler MW, Rogers TJ: Are chemokines the third major system in the brain? J Leukoc Biol 2005;78:1204-1209.
  112. Benamar K, Geller EB, Adler MW: First in vivo evidence for a functional interaction between chemokine and cannabinoid systems in the brain. J Pharmacol Exp Ther 2008;325:641-645.
  113. Benamar K, Yondorf M, Geller EB, Eisenstein TK, Adler MW: Physiological evidence for interaction between the HIV-1 co-receptor CXCR4 and the cannabinoid system in the brain. Br J Pharmacol 2009;157:1225-1231.
  114. Heinisch S, Kirby LG: SDF-1alpha/CXCL12 enhances GABA and glutamate synaptic activity at serotonin neurons in the rat dorsal raphe nucleus. Neuropharmacology 2010;58:501-514.
  115. Hermann GE, Van Meter MJ, Rogers RC: CXCR4 receptors in the dorsal medulla: implications for autonomic dysfunction. Eur J Neurosci 2008;27:855-864.
  116. Lieberam I, Agalliu D, Nagasawa T, Ericson J, Jessell TM: A Cxcl12-CXCR4 chemokine signaling pathway defines the initial trajectory of mammalian motor axons. Neuron 2005;47:667-679.
  117. Odemis V, Lamp E, Pezeshki G, Moepps B, Schilling K, Gierschik P, Littman DR, Engele J: Mice deficient in the chemokine receptor CXCR4 exhibit impaired limb innervation and myogenesis. Mol Cell Neurosci 2005;30:494-505.
  118. Parachikova A, Cotman CW: Reduced CXCL12/CXCR4 results in impaired learning and is downregulated in a mouse model of Alzheimer disease. Neurobiol Dis 2007;28:143-153.
  119. Parachikova A, Nichol KE, Cotman CW: Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiol Dis 2008;30:121-129.
  120. Stumm RK, Rummel J, Junker V, Culmsee C, Pfeiffer M, Krieglstein J, Höllt V, Schulz S: A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J Neurosci 2002;22:5865-5878.
    External Resources
  121. Hill WD, Hess DC, Martin-Studdard A, Carothers JJ, Zheng J, Hale D, Maeda M, Fagan SC, Carroll JE, Conway SJ: SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol 2004;63:84-96.
    External Resources
  122. Robin AM, Zhang ZG, Wang L, Zhang RL, Katakowski M, Zhang L, Wang Y, Zhang C, Chopp M: Stromal cell-derived factor 1alpha mediates neural progenitor cell motility after focal cerebral ischemia. J Cereb Blood Flow Metab 2006;26:125-134.
  123. Chang YC, Shyu WC, Lin SZ, Li H: Regenerative therapy for stroke. Cell Transplant 2007;16:171-181.
    External Resources
  124. Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB, Newcomb EW: Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab Invest 2006;86:1221-1232.
  125. Salcedo R, Oppenheim JJ: Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 2003;10:359-370.
  126. Mirshahi F, Pourtau J, Li H, Muraine M, Trochon V, Legrand E, Vannier J, Soria J, Vasse M, Soria C: SDF-1 activity on microvascular endothelial cells: consequences on angiogenesis in in vitro and in vivo models. Thromb Res 2000;99:587-594.
  127. Salcedo R, Resau JH, Halverson D, Hudson EA, Dambach M, Powell D, Wasserman K, Oppenheim JJ: Differential expression and responsiveness of chemokine receptors (CXCR1-3) by human microvascular endothelial cells and umbilical vein endothelial cells. FASEB J 2000;14:2055-2064.
  128. Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, Anver MR, Kleinman HK, Murphy WJ, Oppenheim JJ: Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol 1999;154:1125-1135.
  129. Hong X, Jiang F, Kalkanis SN, Zhang ZG, Zhang XP, DeCarvalho AC, Katakowski M, Bobbitt K, Mikkelsen T, Chopp M: SDF-1 and CXCR4 are up-regulated by VEGF and contribute to glioma cell invasion. Cancer Lett 2006;236:39-45.
  130. Zagzag D, Krishnamachary B, Yee H, Okuyama H, Chiriboga L, Ali MA, Melamed J, Semenza GL: Stromal cell-derived factor-1alpha and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor. Cancer Res 2005;65:6178-6188.
  131. Tabatabai G, Frank B, Möhle R, Weller M, Wick W: Irradiation and hypoxia promote homing of haematopoietic progenitor cells towards gliomas by TGF-beta-dependent HIF-1alpha-mediated induction of CXCL12. Brain 2006;129:2426-2435.
  132. Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB, Pollack IF, Park DM: Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 2009;28:3949-3959.
  133. Zhao D, Najbauer J, Garcia E, Metz MZ, Gutova M, Glackin CA, Kim SU, Aboody KS: Neural stem cell tropism to glioma: critical role of tumor hypoxia. Mol Cancer Res 2008;6:1819-1829.
  134. Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A: CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 2001;4:702-710.
  135. Calì C, Marchaland J, Regazzi R, Bezzi P: SDF 1-alpha (CXCL12) triggers glutamate exocytosis from astrocytes on a millisecond time scale: imaging analysis at the single-vesicle level with TIRF microscopy. J Neuroimmunol 2008;198:82-91.
  136. Oh JW, Drabik K, Kutsch O, Choi C, Tousson A, Benveniste EN: CXC chemokine receptor 4 expression and function in human astroglioma cells. J Immunol 2001;166:2695-2704.
    External Resources
  137. Croitoru-Lamoury J, Guillemin GJ, Boussin FD, Mognetti B, Gigout LI, Chéret A, Vaslin B, Le Grand R, Brew BJ, Dormont D: Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation. Glia 2003;41:354-370.
  138. Salcedo R, Oppenheim JJ: Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 2003;10:359-370.
  139. Egea V, von Baumgarten L, Schichor C, Berninger B, Popp T, Neth P, Goldbrunner R, Kienast Y, Winkler F, Jochum M, Ries C: TNF-α respecifies human mesenchymal stem cells to a neural fate and promotes migration toward experimental glioma. Cell Death Differ 2011;18:853-863.
  140. Han Y, Wang J, He T, Ransohoff RM: TNF-alpha down-regulates CXCR4 expression in primary murine astrocytes. Brain Res 2001;888:1-10.
  141. Salmaggi A, Gelati M, Pollo B, Frigerio S, Eoli M, Silvani A, Broggi G, Ciusani E, Croci D, Boiardi A, De Rossi M: CXCL12 in malignant glial tumors: a possible role in angiogenesis and cross-talk between endothelial and tumoral cells. J Neurooncol 2004;67:305-317.
  142. McCandless EE, Budde M, Lees JR, Dorsey D, Lyng E, Klein RS: IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. J Immunol 2009;183:613-620.
  143. Odemis V, Moepps B, Gierschik P, Engele J: Interleukin-6 and cAMP induce stromal cell-derived factor-1 chemotaxis in astroglia by up-regulating CXCR4 cell surface expression. Implications for brain inflammation. J Biol Chem 2002;277:39801-39808.
  144. Ping YF, Yao XH, Bian XW, Chen JH, Zhang R, Yi L, Zhou ZH: Activation of CXCR4 in human glioma stem cells promotes tumor angiogenesis. Zhonghua Bing Li Xue Za Zhi 2007;36:179-183.
    External Resources
  145. Ping YF, Yao XH, Chen JH, Liu H, Chen DL, Zhou XD, Wang JM, Bian XW: The anti-cancer compound Nordy inhibits CXCR4-mediated production of IL-8 and VEGF by malignant human glioma cells. J Neurooncol 2007;84:21-29.
  146. Boos L, Szalai AJ, Barnum SR: C3a expressed in the central nervous system protects against LPS-induced shock. Neurosci Lett 2005;387:68-71.
  147. Shinjyo N, Ståhlberg A, Dragunow M, Pekny M, Pekna M: Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. Stem Cells 2009;27:2824-2832.
  148. Zhang J, Sarkar S, Yong VW: The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. Carcinogenesis 2005;26:2069-2077.
  149. Wu M, Chen Q, Li D, Li X, Li X, Huang C, Tang Y, Zhou Y, Wang D, Tang K, Cao L, Shen S, Li G: LRRC4 inhibits human glioblastoma cells proliferation, invasion, and proMMP-2 activation by reducing SDF-1 alpha/CXCR4-mediated ERK1/2 and Akt signaling pathways. J Cell Biochem 2008;103:245-255.
  150. Stremenova J, Krepela E, Mares V, Trim J, Dbaly V, Marek J, Vanickova Z, Lisa V, Yea C, Sedo A: Expression and enzymatic activity of dipeptidyl peptidase-IV in human astrocytic tumours are associated with tumour grade. Int J Oncol 2007;31:785-792.
    External Resources
  151. Christopherson KW 2nd, Hangoc G, Broxmeyer HE: Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells. J Immunol 2002;169:7000-7008.
    External Resources
  152. Busek P, Stremenová J, Krepela E, Sedo A: Modulation of substance P signaling by dipeptidyl peptidase-IV enzymatic activity in human glioma cell lines. Physiol Res 2008;57:443-449.
    External Resources
  153. Nosheny RL, Ahmed F, Yakovlev A, Meyer EM, Ren K, Tessarollo L, Mocchetti I: Brain-derived neurotrophic factor prevents the nigrostriatal degeneration induced by human immunodeficiency virus-1 glycoprotein 120 in vivo. Eur J Neurosci 2007;25:2275-2284.
  154. Ahmed F, Tessarollo L, Thiele C, Mocchetti I: Brain-derived neurotrophic factor modulates expression of chemokine receptors in the brain. Brain Res 2008;1227:1-11.
  155. Esencay M, Newcomb EW, Zagzag D: HGF upregulates CXCR4 expression in gliomas via NF-kappaB: implications for glioma cell migration. J Neurooncol 2010;99:33-40.
  156. Tu H, Zhou Z, Liang Q, Li Z, Li D, Qing J, Wang H, Zhang L: CXCR4 and SDF-1 production are stimulated by hepatocyte growth factor and promote glioma cell invasion. Onkologie 2009;32:331-336.
  157. Cook A, Hippensteel R, Shimizu S, Nicolai J, Fatatis A, Meucci O: Interactions between chemokines: regulation of fractalkine/CX3CL1 homeostasis by SDF/CXCL12 in cortical neurons. J Biol Chem 2010;285:10563-10571.
  158. Alvarez S, Blanco A, Fresno M, Muñoz-Fernández MA: Nuclear factor-kappaB activation regulates cyclooxygenase-2 induction in human astrocytes in response to CXCL12: role in neuronal toxicity. J Neurochem 2010;113:772-783.
  159. Alvarez S, Serramía MJ, Fresno M, Muñoz-Fernández MA: HIV-1 envelope glycoprotein 120 induces cyclooxygenase-2 expression in astrocytoma cells through a nuclear factor-kappaB-dependent mechanism. Neuromolecular Med 2007;9:179-193.
  160. Hagihara K, Zhang EE, Ke YH, Liu G, Liu JJ, Rao Y, Feng GS: Shp2 acts downstream of SDF-1alpha/CXCR4 in guiding granule cell migration during cerebellar development. Dev Biol 2009;334:276-284.
  161. Oh JW, Olman M, Benveniste EN: CXCL12-mediated induction of plasminogen activator inhibitor-1 expression in human CXCR4 positive astroglioma cells. Biol Pharm Bull 2009;32:573-577.
  162. Williams CK, Segarra M, Sierra Mde L, Sainson RC, Tosato G, Harris AL: Regulation of CXCR4 by the Notch ligand delta-like 4 in endothelial cells. Cancer Res 2008;68:1889-1895.
  163. Sciaccaluga M, Fioretti B, Catacuzzeno L, Pagani F, Bertollini C, Rosito M, Catalano M, D'Alessandro G, Santoro A, Cantore G, Ragozzino D, Castigli E, Franciolini F, Limatola C: CXCL12-induced glioblastoma cell migration requires intermediate conductance Ca2+-activated K+ channel activity. Am J Physiol Cell Physiol 2010;299:C175-C184.
  164. Zhou Y, Larsen PH, Hao C, Yong VW: CXCR4 is a major chemokine receptor on glioma cells and mediates their survival. J Biol Chem 2002;277:49481-49487.
  165. Bajetto A, Barbero S, Bonavia R, Piccioli P, Pirani P, Florio T, Schettini G: Stromal cell-derived factor-1alpha induces astrocyte proliferation through the activation of extracellular signal-regulated kinases 1/2 pathway. J Neurochem 2001;77:1226-1236.
  166. Lazarini F, Casanova P, Tham TN, De Clercq E, Arenzana-Seisdedos F, Baleux F, Dubois-Dalcq M: Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes. Eur J Neurosci 2000;12:117-125.
  167. Rubin JB, Kung AL, Klein RS, Chan JA, Sun Y, Schmidt K, Kieran MW, Luster AD, Segal RA: A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci USA 2003;100:13513-13518.
  168. Floridi F, Trettel F, Di Bartolomeo S, Ciotti MT, Limatola C: Signalling pathways involved in the chemotactic activity of CXCL12 in cultured rat cerebellar neurons and CHP100 neuroepithelioma cells. J Neuroimmunol 2003;135:38-46.
  169. Bonavia R, Bajetto A, Barbero S, Pirani P, Florio T, Schettini G: Chemokines and their receptors in the CNS: expression of CXCL12/SDF-1 and CXCR4 and their role in astrocyte proliferation. Toxicol Lett 2003;139:181-189.
  170. Yang L, Jackson E, Woerner BM, Perry A, Piwnica-Worms D, Rubin JB: Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res 2007;67:651-658.
  171. Sato N, Matsubayashi H, Fukushima N, Goggins M: The chemokine receptor CXCR4 is regulated byDNA methylation in pancreatic cancer. Cancer Biol Ther 2005;4:70-76.
  172. Seo J, Kim YO, Jo I: Differential expression of stromal cell-derived factor 1 in human brain microvascular endothelial cells and pericytes involves histone modifications. Biochem Biophys Res Commun 2009;382:519-524.
  173. Barbero S, Bonavia R, Bajetto A, Porcile C, Pirani P, Ravetti JL, Zona GL, Spaziante R, Florio T, Schettini G: Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt. Cancer Res 2003;63:1969-1974.
    External Resources
  174. do Carmo A, Patricio I, Cruz MT, Carvalheiro H, Oliveira CR, Lopes MC: CXCL12/CXCR4 promotes motility and proliferation of glioma cells. Cancer Biol Ther 2010;9:56-65.
  175. Liu XS, Chopp M, Santra M, Hozeska-Solgot A, Zhang RL, Wang L, Teng H, Lu M, Zhang ZG: Functional response to SDF1 alpha through over-expression of CXCR4 on adult subventricular zone progenitor cells. Brain Res 2008;1226:18-26.
  176. Khan MZ, Brandimarti R, Shimizu S, Nicolai J, Crowe E, Meucci O: The chemokine CXCL12 promotes survival of postmitotic neurons by regulating Rb protein. Cell Death Differ 2008;15:1663-1672.
  177. Rosenkranz K, Kumbruch S, Lebermann K, Marschner K, Jensen A, Dermietzel R, Meier C: The chemokine SDF-1/CXCL12 contributes to the ‘homing' of umbilical cord blood cells to a hypoxic-ischemic lesion in the rat brain. J Neurosci Res 2010;88:1223-1233.
  178. Ehtesham M, Winston JA, Kabos P, Thompson RC: CXCR4 expression mediates glioma cell invasiveness. Oncogene 2006;25:2801-2806.
  179. Greenfield JP, Cobb WS, Lyden D: Resisting arrest: a switch from angiogenesis to vasculogenesis in recurrent malignant gliomas. J Clin Invest 2010;120:663-667.
  180. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM: Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest 2010;120:694-705.
  181. Kenig S, Alonso MB, Mueller MM, Lah TT: Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9. Cancer Lett 2010;289:53-61.
  182. Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA: Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res 2006;66:9054-9064.
  183. McMillan KM, Ehtesham M, Stevenson CB, Edgeworth ML, Thompson RC, Price RR: T2 detection of tumor invasion within segmented components of glioblastoma multiforme. J Magn Reson Imaging 2009;29:251-257.
  184. Nimmagadda S, Pullambhatla M, Pomper MG: Immunoimaging of CXCR4 expression in brain tumor xenografts using SPECT/CT. J Nucl Med 2009;50:1124-1130.
  185. Misra P, Lebeche D, Ly H, Schwarzkopf M, Diaz G, Hajjar RJ, Schecter AD, Frangioni JV: Quantitation of CXCR4 expression in myocardial infarction using 99mTc-labeled SDF-1alpha. J Nucl Med 2008;49:963-969.
  186. Park SA, Ryu CH, Kim SM, Lim JY, Park SI, Jeong CH, Jun JA, Oh JH, Park SH, Oh W, Jeun SS: CXCR4-transfected human umbilical cord blood-derived mesenchymal stem cells exhibit enhanced migratory capacity toward gliomas. Int J Oncol 2011;38:97-103.
  187. Tabatabai G, Bähr O, Möhle R, Eyüpoglu IY, Boehmler AM, Wischhusen J, Rieger J, Blümcke I, Weller M, Wick W: Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells. Brain 2005;128:2200-2211.
  188. Redjal N, Chan JA, Segal RA, Kung AL: CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas. Clin Cancer Res 2006;12:6765-6771.
  189. Hägerstrand D, Hesselager G, Achterberg S, Wickenberg Bolin U, Kowanetz M, Kastemar M, Heldin CH, Isaksson A, Nistér M, Ostman A: Characterization of an imatinib-sensitive subset of high-grade human glioma cultures. Oncogene 2006;25:4913-4922.
  190. Kast RE: Profound blockage of CXCR4 signaling at multiple points using the synergy between plerixafor, mirtazapine, and clotrimazole as a new glioblastoma treatment adjunct. Turk Neurosurg 2010;20:425-429.
  191. Hatse S, Princen K, De Clercq E, Rosenkilde MM, Schwartz TW, Hernandez-Abad PE, Skerlj RT, Bridger GJ, Schols D: AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor. Biochem Pharmacol 2005;70:752-761.
  192. Gravel S, Malouf C, Boulais PE, Berchiche YA, Oishi S, Fujii N, Leduc R, Sinnett D, Heveker N: The peptidomimetic CXCR4 antagonist TC14012 recruits beta-arrestin to CXCR7: roles of receptor domains. J Biol Chem 2010;285:37939-37943.
  193. Cheng Z, Zhou S, Wang X, Xie F, Wu H, Liu G, Wang Q, Chen Y, Hu Y, Lu B, Zhang X: Characterization and application of two novel monoclonal antibodies against human CXCR4: cell proliferation and migration regulation for glioma cell line in vitro by CXCR4/SDF-1alpha signal. Hybridoma (Larchmt) 2009;28:33-41.
  194. Kottke T, Hall G, Pulido J, Diaz RM, Thompson J, Chong H, Selby P, Coffey M, Pandha H, Chester J, Melcher A, Harrington K, Vile R: Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice. J Clin Invest 2010;120:1551-1560.
  195. Müller FJ, Snyder EY, Loring JF: Gene therapy: can neural stem cells deliver? Nat Rev Neurosci 2006;7:75-84.
  196. Tyler MA, Ulasov IV, Sonabend AM, Nandi S, Han Y, Marler S, Roth J, Lesniak MS: Neural stem cells target intracranial glioma to deliver an oncolytic adenovirus in vivo. Gene Ther 2009;16:262-278.
  197. Ehtesham M, Yuan X, Kabos P, Chung NH, Liu G, Akasaki Y, Black KL, Yu JS: Glioma tropic neural stem cells consist of astrocytic precursors and their migratory capacity is mediated by CXCR4. Neoplasia 2004;6:287-293.
    External Resources
  198. Sonabend AM, Ulasov IV, Tyler MA, Rivera AA, Mathis JM, Lesniak MS: Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma. Stem Cells 2008;26:831-841.
  199. Tseng D, Vasquez-Medrano DA, Brown JM: Targeting SDF-1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas. Br J Cancer 2011;104:1805-1809.
  200. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95.
  201. Wong D, Korz W: Translating an antagonist of chemokine receptor CXCR4: from bench to bedside. Clin Cancer Res 2008;14:7975-7980.
  202. Hattermann K, Mentlein R, Held-Feindt J: CXCL12 mediates apoptosis resistance in rat C6 glioma cells. Oncol Rep 2012;27:1348-1352.
  203. Meincke M, Tiwari S, Hattermann K, Kalthoff H, Mentlein R: Near-infrared molecular imaging of tumors via chemokine receptors CXCR4 and CXCR7. Clin Exp Metastasis 2011;28:713-720.
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