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Fig. 1 | Cell Communication and Signaling

Fig. 1

From: The role of TGF-β and its crosstalk with RAC1/RAC1b signaling in breast and pancreas carcinoma

Fig. 1

Schematic involvement of TGF-β and RAC1/RAC1b during metastatic steps. Metastasizing tumor cells from primary tumor site with self-renewing cancer stem-like cells undergo EMT and disseminate to distant organs (DTCs) after transendothelial migration as circulating tumor cells (CTCs) (modified according to Pantel and Brakenhoff [109]). TGF-β and RAC1/RAC1b play important roles during EMT and are also associated with further steps during metastasis. In particular, TGF-β promotes the dialogue of cancer cells with non-neoplastic cells of the tumor microenvironment such as epithelial, stromal and immune cells to promote EMT by down-modulation of E-cadherin expression and induction of matrix metalloproteinase (MMP) production and release. Moreover, TGF-β contributes to collective-to-single cell movement. In addition, increased TGF-β levels in the circulation were suggested to correlate with elevated appearance of CTCs and predominant formation of lung metastases in breast cancer patients leading to poor prognosis [110]. The RHO GTPase RAC1 is involved in the control of important cellular functions such as adhesion, motility, and proliferative capacity. Hyperactivation of RAC1 is detected in the majority of breast and pancreatic cancers in which RAC1 can transduce signals from different receptors, including those for TGF-β. RAC1b has been shown to negatively regulate RAC1 activity [85] as well as TGF-β1-dependent cell motility, SMAD2/3 C-terminal phosphorylation and TGF-β/SMAD-mediated transcription [93] which leads to the hypothesis that RAC1 and RAC1b have antagonistic roles in the regulation of TGF-β-induced EMT and MET

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