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Regulation of Extracellular Matrix Remodeling following Transforming Growth Factor-β1/Epidermal Growth Factor-Stimulated Epithelial-Mesenchymal Transition in Human Premalignant Keratinocytes

Regulation of Extracellular Matrix Remodeling following Transforming Growth Factor-β1/Epidermal... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cells Tissues Organs Karger

Regulation of Extracellular Matrix Remodeling following Transforming Growth Factor-β1/Epidermal Growth Factor-Stimulated Epithelial-Mesenchymal Transition in Human Premalignant Keratinocytes

Cells Tissues Organs , Volume 185 (1-3): 7 – Jun 1, 2007

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References (85)

Publisher
Karger
Copyright
© 2007 S. Karger AG, Basel
ISSN
1422-6405
eISSN
1422-6421
DOI
10.1159/000101312
Publisher site
See Article on Publisher Site

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.

Journal

Cells Tissues OrgansKarger

Published: Jun 1, 2007

Keywords: Matrix metalloproteinase; Extracellular matrix; Epithelial-mesenchymal transition; Transforming growth factor-β; Epidermal growth factor

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