Pathophysiology of Post-Transplantation Cancer

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DESCRIPTION (provided by applicant): Chemokines are well established to function in the recruitment of leucocytes into an allograft, and may facilitate graft dysfunction and rejection. However, some recent studies have demonstrated that chemokines may also be functional in tumor development. The chemokine CXCL10, also known as IP-10 is a T-cell chemoattractant, and is classically thought to have tumor inhibitory properties. Nevertheless, paradoxically, some recent reports have indicated that CXCL10 can also promote tumor growth. We recently discovered that this controversy in the function of CXCL10 is in part related to alternative splicing of its receptor (CXCR3). CXCR3 exists as two novel variants called CXCR3-A and CXCR3-B, having different functions; CXCR3-A promotes chemotaxis and cell proliferation, whereas CXCR3-B signals for growth inhibition. Our recent studies identified that activation of the Ras signaling pathway in human cancer cells promotes the overexpression of CXCL10, and also downregulates the expression of the growth inhibitory receptor CXCR3-B in these cells. We also demonstrated that in absence of CXCR3-B, there is a marked increase in cancer cell proliferation, likely mediated through CXCR3-A. It is now established that the development of cancer is a major and increasing problem following solid organ transplantation, and some forms of cancer (e.g., kidney cancer) increase markedly after kidney transplantation. Moreover, different oncogenes including Ras may become activated during the post-transplantation period. Our preliminary studies have shown that the immunosuppressive agent Cyclosporine A (CsA) (known to activate Ras, and to promote tumor growth) can induce CXCL10, and can also markedly downregulate the expression of CXCR3-B in human renal epithelial cells. We propose that chemokines, in particular the CXCR3-binding chemokine CXCL10 and its receptor CXCR3, which are significantly increased during the post-transplantation period, may mechanistically "link" alloimmunity and tumor development. Our hypothesis is that Ras-induced overexpression of the CXCR3-binding chemokine CXCL10, and the differential distribution and signaling through CXCR3 splice variants (CXCR3-A and CXCR3-B) mediate the development of renal tumors, having direct relevance to post-transplantation cancer. Our Specific Aims evaluate the differential signaling mechanisms mediated through CXCR3-A and CXCR3-B in human renal cancer cells (Aim 1), the mechanism whereby CsA and Ras inhibit CXCR3-B, and promote CXCL10 expression (Aim 2), and the in vivo significance of CXCR3 splice variants in the development of renal cancer, and the phenotypic profiles of CXCR3-A and CXCR3-B, and their ligands in tumor tissues obtained from transplant and non-transplant patients (Aim 3). PUBLIC HEALTH RELEVANCE: This research proposal focuses to study a mechanism by which the tumor growth may be enhanced in the patients with organ transplantation. Our objective is to evaluate the role of the chemokine CXCL10 and its receptor splice variants (CXCR3-A and CXCR3-B) in the development of post-transplantation cancer.