Paper

Regulation of Extracellular Matrix Remodeling following Transforming Growth Factor-β1/Epidermal Growth Factor-Stimulated Epithelial-Mesenchymal Transition in Human Premalignant Keratinocytes
Cynthia E. Wilkins-Port, Paul J. Higgins

Center for Cell Biology and Cancer Research, Albany Medical College, Albany, N.Y., USA

Address of Corresponding Author

Cells Tissues Organs 2007;185:116-122 (DOI: 10.1159/000101312)

  Key Words

• Epithelial-mesenchymal transition
• Transforming growth factor-β
• Epidermal growth factor
• Matrix metalloproteinase
• Extracellular matrix

  Abstract

During tumor progression, malignant cells exploit critical developmental and tissue remodeling programs, often promoting a plastic phenotype referred to as an epithelial-mesenchymal transition (EMT). Autocrine/paracrine signaling due to tumor microenvironment cytokines, such as members of the transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) families, largely regulates the morphological and invasive phases of the EMT phenotype. Notably, epithelial cell initiation often coincides with a switch in the response of these cells to TGF-β and is concomitant with EGF receptor amplification. Modeling these events, we have observed that premalignant human keratinocytes, HaCaTs, acquire a highly motile and scattered phenotype indicative of EMT following stimulation with TGF-β1 and EGF. TGF-β1 and EGF have been shown to upregulate a number of matrix metalloproteinases (MMP) in epithelial cells, which may in turn play a role in developing metastatic potential in these cells. We have established that an increase in MMP-10 expression occurs following treatment of HaCaT cells with a combination of TGF-β1 and EGF. This increase in MMP-10 expression paralleled the development of a collagenolytic phenotype that was sensitive to components of the plasminogen activation system, including the plasminogen activator inhibitor type-1 (PAI-1). Significantly high levels of MMP-10 have been detected in squamous cell carcinomas of the head and neck, esophagus, oral cavity and skin. Importantly, TGF-β1 in addition to upregulating MMP-10 has been shown to upregulate PAI-1 expression in HaCaT cells. Taken together, these observations suggest that TGF-β1 and EGF play a complex role in modulating proteolytic and transitional events such as EMT that may facilitate the progression of human premalignant epithelial cells toward a more invasive phenotype.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Dr. Paul J. Higgins
Center for Cell Biology and Cancer Research
47 New Scotland Avenue, mail code 165
Albany, NY 12208 (USA)
Tel. +1 518 262 5651, Fax +1 518 262 5669, E-Mail higginp@mail.amc.edu

  Article Information

Number of Print Pages : 7
Number of Figures : 2, Number of Tables : 0, Number of References : 65