Tumor suppressor activity of the TGF-beta pathway in human cancers.

The TGF-betas are a family of cytokines with antiproliferative activity on many cell types. Recent findings demonstrate that the TGF-beta receptor complex functions as a tumor suppressor gene in human malignancy. Somatic mutations of the type II subunit of the TGF-beta receptor (RII) have been demonstrated in several different tumor types. RII frameshift mutations within a short coding region polyadenine repeat are particularly characteristic of colon and gastric cancers that also demonstrate the phenotype of microsatellite instability (RER cancers). These and other mutations as in the type I receptor (RI) are associated with both loss of cell surface TGF beta receptors and with resistance of the cancer cells to TGF-beta-induced growth inhibition. Restoration of receptor expression by gene transfection reverses the transformed phenotype in cancer cells that lacked functional RII or RI. These receptors and, by implication, TGF-beta as well as its complete signalling pathway, are thus new and novel additions to the family of human tumor suppressor genes.