Abstract
Abstract Introduction. Renal cell carcinoma (RCC) is the one of the most common cancers diagnosed in adult men with more than 40000 new cases annually. Recurrence or metastasis of the disease occurs in more than 30% of patients and death from disease occurs in most of these patients due to limited therapeutic options. Clearly, a better understanding of factors contributing to RCC metastasis might improve therapeutic development and patient outcomes. One of the steps required for tumor cell progression from localized disease to metastatic disease is the acquisition of invasive abilities through epithelial to mesenchymal transition (EMT). EMT promotes loss of epithelial markers by downregulation of E-cadherin, gain of mesenchymal markers like Vimentin, and N-cadherin, and cytoskeletal rearrangement that enables cells to leave the primary site and intravasate into the blood or lymphatic systems and thereby colonize distant sites. Metastasis and colonization are highly directed mechanisms in which cancer cells migrate toward specific preferred organs that express specific protein receptors. One of these receptors is CXCR4, which is upregulated in advanced cancer including RCC and is correlated with poor survival. In this study we explored the hypothesis that CXCR4/CXCL12 signaling promotes migratory ability by inducing EMT in vitro in the RCC cell lines Caki-2 and 786-0. Methods. To pursue these studies we utilized in vitro mammalian cell culture, cell proliferation (WST) assays, cell migration (scratch) assays, and protein analysis methods including immunoblot and immunofluorescence. Results. These studies showed that RCC cell lines express CXCR4 that is activated by CXCL12 to induce cellular proliferation and promote a wound healing migratory response dependent on EMT cytoskeletal rearrangement by Rho GTPases. Moreover, CXCR4/CXCL12 induces down-regulation of E-cadherin, up-regulation of vimentin, N-cadherin and the upregulation of EMT transcription factors SLUG/SNAIL, consistent with EMT signaling activation. Lastly, CXCR4/CXCL12 activation promotes phosphorylation of AKT and ERK, suggesting that these signaling pathways are coupled to CXCR4/CXCL12-mediated RCC progression. Conclusions. Our findings suggest that CXCR4/CXCL12 activation in RCC has a pivotal role in EMT induction by the acquisition of a migratory and invasive phenotype. Understanding the underlying signaling pathways employed by the CXCL12/CXCR4 axis may shed new light on the migration/ invasion mechanisms that allow RCC cells to spread to distant organs and assist with the design and testing of new therapeutic strategies to treat advanced metastatic RCC. Citation Format: Alisa Zhilin-Roth, Jill A. Macoska. The CXCL12/CXCR4 axis drives epithelial-mesenchymal transition in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2021.
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call