The Role of TGFβ Signaling in Squamous Cell Cancer: Lessons from Mouse Models

TGFβ1 is a member of a large growth factor family including activins/inhibins and bone morphogenic proteins (BMPs) that have a potent growth regulatory and immunomodulatory functions in normal skin homeostasis, regulation of epidermal stem cells, extracellular matrix production, angiogenesis, and inflammation. TGFβ signaling is tightly regulated in normal tissues and becomes deregulated during cancer development in cutaneous SCC and many other solid tumors. Because of these diverse biological processes regulated by TGFβ1, this cytokine and its signaling pathway appear to function at multiple points during carcinogenesis with distinct effects. The mouse skin carcinogenesis model has been a useful tool to dissect the function of this pathway in cancer pathogenesis, with transgenic and null mice as well as small molecule inhibitors to alter the function of the TGFβ1 pathway and assess the effects on cancer development. This paper will review data on changes in TGFβ1 signaling in human SCC primarily HNSCC and cutaneous SCC and different mouse models that have been generated to investigate the relevance of these changes to cancer. A better understanding of the mechanisms underlying the duality of TGFβ1 action in carcinogenesis will inform potential use of this signaling pathway for targeted therapies.