Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer
2007 (English)In: Biochimica et Biophysica Acta, ISSN 0006-3002, Vol. 1775, no 1, 21-62 p.Article, review/survey (Refereed) Published
Transforming growth factor-beta (TGF-beta) is a secreted polypeptide that signals via receptor serine/threonine kinases and intracellular Smad effectors. TGF-beta inhibits proliferation and induces apoptosis in various cell types, and accumulation of loss-of-function mutations in the TGF-beta receptor or Smad genes classify the pathway as a tumor suppressor in humans. In addition, various oncogenic pathways directly inactivate the TGF-beta receptor-Smad pathway, thus favoring tumor growth. On the other hand, all human tumors overproduce TGF-beta whose autocrine and paracrine actions promote tumor cell invasiveness and metastasis. Accordingly, TGF-beta induces epithelial-mesenchymal transition, a differentiation switch that is required for transitory invasiveness of carcinoma cells. Tumor-derived TGF-beta acting on stromal fibroblasts remodels the tumor matrix and induces expression of mitogenic signals towards the carcinoma cells, and upon acting on endothelial cells and pericytes, TGF-beta regulates angiogenesis. Finally, TGF-beta suppresses proliferation and differentiation of lymphocytes including cytolytic T cells, natural killer cells and macrophages, thus preventing immune surveillance of the developing tumor. Current clinical approaches aim at establishing novel cancer drugs whose mechanisms target the TGF-beta pathway. In conclusion, TGF-beta signaling is intimately implicated in tumor development and contributes to all cardinal features of tumor cell biology.
Place, publisher, year, edition, pages
2007. Vol. 1775, no 1, 21-62 p.
Cancer, Epithelial–mesenchymal transition, Metastasis, Smad, TGF-β, Tumor suppressor
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-21664DOI: 10.1016/j.bbcan.2006.06.004ISI: 000243317700003PubMedID: 16904831OAI: oai:DiVA.org:uu-21664DiVA: diva2:49437