Mechanisms of the epithelial-mesenchymal transition by TGF-beta.
The formation of epithelial cell barriers results from the defined spatiotemporal differentiation of stem cells into a specialized and polarized epithelium, a process termed mesenchymal-epithelial transition. The reverse process, epithelial-mesenchymal transition (EMT), is a metastable process that enables polarized epithelial cells to acquire a motile fibroblastoid phenotype. Physiological EMT also plays an essential role in promoting tissue healing, remodeling or repair in response to a variety of pathological insults. On the other hand, pathophysiological EMT is a critical step in mediating the acquisition of metastatic phenotypes by localized carcinomas. Although metastasis clearly is the most lethal aspect of cancer, our knowledge of the molecular events that govern its development, including those underlying EMT, remain relatively undefined. Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that oversees and directs all aspects of cell development, differentiation and homeostasis, as well as suppresses their uncontrolled proliferation and transformation. Quite dichotomously, tumorigenesis subverts the tumor suppressing function of TGF-beta, and in doing so, converts TGF-beta to a tumor promoter that stimulates pathophysiological EMT and metastasis. It therefore stands to reason that determining how TGF-beta induces EMT in developing neoplasms will enable science and medicine to produce novel pharmacological agents capable of preventing its ability to do so, thereby improving the clinical course of cancer patients. Here we review the cellular, molecular and microenvironmental mechanisms used by TGF-beta to mediate its stimulation of EMT in normal and malignant cells.
Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045, USA.
Michael K
MK
Wendt
Tressa M
TM
Allington
William P
WP
Schiemann
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D004848:Epithelium / Q000473:pathology*; D006801:Humans; D008648:Mesoderm / Q000473:pathology*; D008679:Metaplasia; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016212:Transforming Growth Factor beta