Suppressor and oncogenic roles of transforming growth factor-β and its signaling pathways in tumorigenesis

Transforming growth factor-β (TGF-β) has been implicated in oncogenesis since the time of its discovery almost 20 years ago. The complex, multifunctional activities of TGF-β endow it with both tumor suppressor and tumor promoting activities, depending on the stage of carcinogenesis and the responsivity of the tumor cell. Dysregulation or alteration of TGF-β signaling in tumorigenesis can occur at many different levels, including activation of the ligand, mutation or transcriptional suppression of the receptors, or alteration of downstream signal transduction pathways resulting from mutation or changes in expression patterns of signaling intermediates or from changes in expression of other proteins which modulate signaling. New insights into signaling from the TGF-β receptors, including the identification of Smad signaling pathways and their interaction with mitogen-activated protein (MAP) kinase pathways, are providing an understanding of the changes involved in the change from tumor suppressor to tumor promoting activities of TGF-β. It is now appreciated that loss of sensitivity to inhibition of growth by TGF-β by most tumor cells is not synonymous with complete loss of TGF-β signaling but rather suggests that tumor cells gain advantage by selective inactivation of the tumor suppressor activities of TGF-β with retention of its tumor promoting activities, especially those dependent on cross talk with MAP kinase pathways and AP-1. © 2001 Academic Press.