A New Switch for TGFß in Cancer.

The TGFß cytokine plays dichotomous roles during tumor progression. In normal and premalignant cancer cells, the TGFß signaling pathway inhibits proliferation and promotes cell-cycle arrest and apoptosis. However, the activation of this pathway in late-stage cancer cells could facilitate the epithelial-to-mesenchymal transition, stemness, and mobile features to enhance tumorigenesis and metastasis. The opposite functions of TGFß signaling during tumor progression make it a challenging target to develop anticancer interventions. Nevertheless, the recent discovery of cellular contextual determinants, especially the binding partners of the transcription modulators Smads, is critical to switch TGFß responses from proapoptosis to prometastasis. In this review, we summarize the recently identified contextual determinants (such as PSPC1, KLF5, 14-3-3ζ, C/EBPß, and others) and the mechanisms of how tumor cells manage the context-dependent autonomous TGFß responses to potentiate tumor progression. With the altered expression of some contextual determinants and their effectors during tumor progression, the aberrant molecular prometastatic switch might serve as a new class of theranostic targets for developing anticancer strategies.