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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Salnikow, Konstantin
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Children's Hospital Boston
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Balan, Murugabaskar; Mier y Teran, Eduardo; Waaga-Gasser, Ana Maria et al. (2015) Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J Biol Chem 290:8110-20
Balan, Murugabaskar; Pal, Soumitro (2014) A novel CXCR3-B chemokine receptor-induced growth-inhibitory signal in cancer cells is mediated through the regulation of Bach-1 protein and Nrf2 protein nuclear translocation. J Biol Chem 289:3126-37
Banerjee, Pallavi; Basu, Aninda; Arbiser, Jack L et al. (2013) The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways. Cancer Lett 338:292-9
Basu, Aninda; Banerjee, Pallavi; Pal, Soumitro (2012) Critical role of mTOR in calcineurin inhibitor-induced renal cancer progression. Cell Cycle 11:633-4
Basu, Aninda; Liu, Tao; Banerjee, Pallavi et al. (2012) Effectiveness of a combination therapy using calcineurin inhibitor and mTOR inhibitor in preventing allograft rejection and post-transplantation renal cancer progression. Cancer Lett 321:179-86
Banerjee, Pallavi; Basu, Aninda; Wegiel, Barbara et al. (2012) Heme oxygenase-1 promotes survival of renal cancer cells through modulation of apoptosis- and autophagy-regulating molecules. J Biol Chem 287:32113-23
Banerjee, Pallavi; Basu, Aninda; Datta, Dipak et al. (2011) The heme oxygenase-1 protein is overexpressed in human renal cancer cells following activation of the Ras-Raf-ERK pathway and mediates anti-apoptotic signal. J Biol Chem 286:33580-90
Basu, Aninda; Banerjee, Pallavi; Contreras, Alan G et al. (2011) Calcineurin inhibitor-induced and Ras-mediated overexpression of VEGF in renal cancer cells involves mTOR through the regulation of PRAS40. PLoS One 6:e23919
Basu, Aninda; Datta, Dipak; Zurakowski, David et al. (2010) Altered VEGF mRNA stability following treatments with immunosuppressive agents: implications for cancer development. J Biol Chem 285:25196-202
Datta, Dipak; Banerjee, Pallavi; Gasser, Martin et al. (2010) CXCR3-B can mediate growth-inhibitory signals in human renal cancer cells by down-regulating the expression of heme oxygenase-1. J Biol Chem 285:36842-8

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