Actions of TGF-beta as tumor suppressor and pro-metastatic factor in human cancer.
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.
Pardali
Katerina
K
Ludwig Institute for Cancer Research, Box 595 Biomedical Center, Uppsala University, SE-751 24 Uppsala, Sweden.
Moustakas
Aristidis
A
D000818:Animals; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002273:Carcinogens; D002453:Cell Cycle / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D008648:Mesoderm / Q000473:pathology; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000503:physiopathology; D009369:Neoplasms / Q000098:blood supply; D009389:Neovascularization, Pathologic; D009857:Oncogenes / Q000502:physiology; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051785:Smad Proteins / Q000235:genetics / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D000912:Antibodies, Neoplasm; D002273:Carcinogens; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins