TGF--Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis

Transforming growth factor (TGF-) is a secreted cytokine that regulates cell proliferation, migration, and the differentiation of a plethora of different cell types. Consistent with these findings, TGF- plays a key role in controlling embryogenic development, inflammation, and tissue repair, as well as in maintaining adult tissue homeostasis. TGF- elicits a broad range of context-dependent cellular responses, and consequently, alterations in TGF- signaling have been implicated in many diseases, including cancer. During the early stages of tumorigenesis, TGF- acts as a tumor suppressor by inducing cytostasis and the apoptosis of normal and premalignant cells. However, at later stages, when cancer cells have acquired oncogenic mutations and/or have lost tumor suppressor gene function, cells are resistant to TGF--induced growth arrest, and TGF- functions as a tumor promotor by stimulating tumor cells to undergo the so-called epithelial-mesenchymal transition (EMT). The latter leads to metastasis and chemotherapy resistance. TGF- further supports cancer growth and progression by activating tumor angiogenesis and cancer-associated fibroblasts and enabling the tumor to evade inhibitory immune responses. In this review, we will consider the role of TGF- signaling in cell cycle arrest, apoptosis, EMT and cancer cell metastasis. In particular, we will highlight recent insights into the multistep and dynamically controlled process of TGF--induced EMT and the functions of miRNAs and long noncoding RNAs in this process. Finally, we will discuss how these new mechanistic insights might be exploited to develop novel therapeutic interventions.