title: The role of small GTPases of the Rho/Rac family in TGF-β-induced EMT and cell motility in cancer.
abstract: This article focuses on the role of Rho family GTPases, particularly Rac1 and Rac1b in TGF-β-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-β, 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-β 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-β signaling, at least in pancreatic carcinoma cells. Given the tumor-promoting role of TGF-β in late-stage carcinomas and the intimate crosstalk of Rho/Rac1/Rac1b and TGF-β signaling in various tumor cell responses, targeting specific Rho GTPases may allow for selective interference with prooncogenic TGF-β responses to aid in anticancer treatments. Developmental Dynamics 247:451-461, 2018. © 2017 Wiley Periodicals, Inc.
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, and University of Lübeck, Lübeck, Germany.|Department of General and Thoracic Surgery, UKSH, Campus Kiel, Kiel, Germany.
authors.forename: Hendrik
authors.identifier: http://orcid.org/0000-0002-7552-2087
authors.initials: H
authors.lastname: Ungefroren
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, and University of Lübeck, Lübeck, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Witte
authors.affiliation: First Department of Medicine, University Hospital Schleswig-Holstein (UKSH), Campus Lübeck, and University of Lübeck, Lübeck, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
mesh_terms: D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology*; D009369:Neoplasms / Q000473:pathology*; D020239:Receptor Cross-Talk; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D020559:Monomeric GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins
keywords: Epithelial-mesenchymal transition; Rac1; Rac1b; Rho; Rho GTPases; TGF-β; cell signaling; invasion; metastasis; pancreatic cancer