Mechanisms of the Epithelial–Mesenchymal Transition by TGF-β

Abstract

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-β (TGF-β) 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-β, and in doing so, converts TGF-β to a tumor promoter that stimulates pathophysiological EMT and metastasis. It therefore stands to reason that determining how TGF-β 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-β to mediate its stimulation of EMT in normal and malignant cells.

Keywords:

• epithelial-mesenchymal transition
• metastasis
• signal transduction
• transforming growth factor-β
• tumor microenvironment

Financial & competing interests disclosure

William P Schiemann was supported by grants from the National Institutes of Health (CA114039 and CA129359), the Komen Foundation (BCTR0706967), and the Department of Defense (BC084651); Michael K Wendt was supported by the American Cancer Society (PF-09–120–101-CS); and Tressa M Allington was supported by the Department of Defense (BC083323). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Acknowledgements

We thank members of the Schiemann Laboratory for critical comments and reading of the manuscript.

Additional information

Funding

William P Schiemann was supported by grants from the National Institutes of Health (CA114039 and CA129359), the Komen Foundation (BCTR0706967), and the Department of Defense (BC084651); Michael K Wendt was supported by the American Cancer Society (PF-09–120–101-CS); and Tressa M Allington was supported by the Department of Defense (BC083323). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.