The role of small GTPases of the Rho/Rac family in TGF--induced EMT and cell motility in cancer

This article focuses on the role of Rho family GTPases, particularly Rac1 and Rac1b in TGF--induced epithelial-mesenchymal transition (EMT) and EMT-associated responses such as cell migration, invasion, and metastasis in cancer. EMT is considered a prerequisite for cells to adopt a motile and invasive phenotype and eventually become metastatic. A major regulator of EMT and metastasis in cancer is TGF-, and its specific functions on tumor cells are mediated beside Smad proteins and mitogen-activated protein kinases (MAPKs) by small GTPases of the Rho/Rac1 family. Available data point to extensive signaling crosstalk between TGF- and various Rho GTPases, and in particular a synergistic role of Rho and Rac1 during EMT and cell motility in normal and neoplastic epithelial cells. In contrast, the Rac1-related isoform, Rac1b, emerges as an endogenous inhibitor of Rac1 in TGF- signaling, at least in pancreatic carcinoma cells. Given the tumor-promoting role of TGF- in late-stage carcinomas and the intimate crosstalk of Rho/Rac1/Rac1b and TGF- signaling in various tumor cell responses, targeting specific Rho GTPases may allow for selective interference with prooncogenic TGF- responses to aid in anticancer treatments. Developmental Dynamics 247:451-461, 2018. (c) 2017 Wiley Periodicals, Inc.