The relevance of the TGF-β Paradox to EMT-MET programs

Cancer Lett. 2013 Nov 28;341(1):30-40. doi: 10.1016/j.canlet.2013.02.048. Epub 2013 Mar 5.

Abstract

The role of transforming growth factor-β (TGF-β) during tumorigenesis is complex and paradoxical, reflecting its ability to function as a tumor suppressor in normal and early-stage cancers, and as a tumor promoter in their late-stage counterparts. The switch in TGF-β function is known as the "TGF-β Paradox," whose manifestations are intimately linked to the initiation of epithelial-mesenchymal transition (EMT) programs in developing and progressing carcinomas. Indeed, as carcinoma cells emerge from EMT programs stimulated by TGF-β, they readily display a variety of acquired phenotypes that provide a selective advantage to growing carcinomas, including (i) enhanced cell migration and invasion; (ii) heightened resistance to cytotoxic agents, targeted chemotherapeutic, and radiation treatments; and (iv) boosted expansion of cancer-initiating and stem-like cell populations that underlie tumor metastasis and disease recurrence. At present, the molecular, cellular, and microenvironmental mechanisms that enable post-EMT and metastatic carcinoma cells to hijack the oncogenic activities of TGF-β remain incompletely understood. Additionally, the molecular mechanisms that counter EMT programs and limit the aggressiveness of late-stage carcinomas, events that transpire via mesenchymal-epithelial transition (MET) reactions, also need to be further elucidated. Here we review recent advances that provide new insights into how TGF-β promotes EMT programs in late-stage carcinoma cells, as well as how these events are balanced by MET programs during the development and metastatic progression of human carcinomas.

Keywords: Epithelial plasticity; Metastasis; TGF-β.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Alternative Splicing
  • Animals
  • Bone Morphogenetic Proteins / metabolism
  • Cell Hypoxia
  • DNA-Binding Proteins / metabolism
  • Epithelial-Mesenchymal Transition / physiology*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Heat-Shock Proteins / metabolism
  • Humans
  • Integrins / metabolism
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Proto-Oncogene Proteins c-abl / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*

Substances

  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • ERP29 protein, human
  • GRHL2 protein, human
  • Heat-Shock Proteins
  • Integrins
  • MIRN200 microRNA, human
  • MicroRNAs
  • Transcription Factors
  • Transforming Growth Factor beta
  • Proto-Oncogene Proteins c-abl