Paradoxical roles of TGF-ß signaling in suppressing and promoting squamous cell carcinoma.

ABSTRACT

Transforming growth factor ß (TGF-ß) signaling either promotes or inhibits tumor formation and/or progression of many cancer types including squamous cell carcinoma (SCC). Canonical TGF-ß signaling is mediated by a number of downstream proteins including Smad family proteins. Alterations in either TGF-ß or Smad signaling can impact cancer. For instance, defects in TGF-ß type I and type II receptors (TGF-ßRI and TGF-ßRII) and in Smad2/3/4 could promote tumor development. Conversely, increased TGF-ß1 and activated TGF-ßRI and Smad3 have all been shown to have tumor-promoting effects in experimental systems of human and mouse SCCs. Among TGF-ß/Smad signaling, only TGF-ßRII or Smad4 deletion in mouse epithelium causes spontaneous SCC in the mouse model, highlighting the critical roles of TGF-ßRII and Smad4 in tumor suppression. Herein, we review the dual roles of the TGF-ß/Smad signaling pathway and related mechanisms in SCC, highlighting the potential benefits and challenges of TGF-ß/Smad-targeted therapies.