TGFβ and its Smad Connection to Cancer

The resistance to growth inhibition commonly observed in a variety of TGFβ disabled human cancers, the potential role of TGFβ in the exacerbation of malignancy and the effects of TGFβ in suppressing the immune system, all emphasize the importance of pathways mediated by this polypeptide to the neoplastic process. Early investigations to understand the molecular basis of cancer due to defects in TGFβ signaling were concentrated on examining the abundance of biologically active TGFβ and its binding to TGFβ receptors. However, major breakthroughs in understanding the molecular basis of the TGFβ mediated effects in cancer came from genetic evidence for inactivation of the various players in its signaling cascade. The vast majority of current evidence is derived from the identification of mutations causing structural defects in TGFβ receptors and Smad genes, the downstream effectors of the TGFβ signaling pathway that have emerged from the analysis of human cancers. The involvement of Smads at the receptor level upon activation by a TGFβ bound receptor, their participation in signal transmission to the nucleus and their direct roles in the regulation of target genes have made the various Smad genes critical targets for inactivation of TGFβ signaling in cancer. To date, eight human homologues of the Smad genes have been identified and are classified into three distinct classes based on their structure and function. In this review, we discuss TGFβ signaling via the Smads and the known and predicted points at which TGFβ signaling could become altered in human cancer.