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

Abstract

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.

Figure 1

Schematic of TGFβ1 signaling pathway and its regulation. TGFβ1 is secreted and sequestered in the extracellular matrix as a biologically inactive complex composed of the TGFβ1 peptide linked to the latency-associated peptide (LAP) and a member of the latent TGFβ-binding protein (LTBP) family. Activation of latent TGFβ1 allows binding of active peptide dimer to TβRII and formation of a heterotetrameric receptor complex Between TβRI and TβRII. Coreceptors such as betaglycan act to enhance TGFβ binding to its receptors. TβRII, phosphorylates the cytoplasmic domain of TβRI and activates its serine-threonine kinase activity towards the R-Smads, Smad2, or Smad3, Phosphorylation of an R-Smad for allows complex formation with Smad4 and translocation to the nucleus, where binding to SBE target sites in gene promoters activates transcription with many other cofactors. Dephosphorylation of R-Smads by Smad phosphatases such as PPM1A attenuate signaling and cause Smads to recycle to the cytoplasm. Smad7 can block type I receptor phosphorylation of R-Smads and in conjunction with E3 ubiquitin ligases such as Smurf1 cause polyubiquitination and degradation of TβRI. Smurf1 and similar proteins have also been implicated in degradation of R-Smads.