Chemokines as therapeutic targets in renal cell carcinoma

Abstract

Targeting novel pathways associated with tumor angiogenesis, invasion and immunity, may lead to improvement in patient outcomes for renal cell carcinoma. Chemokines potentiate tumor growth, metastasis, angiogenesis and immune evasion through interactions with stromal cells and neoplastic cells. Further understanding of the mechanisms involved in chemokine-mediated angiogenesis and metastasis may lead to improved therapeutic strategies in this disease. Interactions between chemokine expression and signaling, and the VEGF and hypoxia-inducible factor pathways offer important opportunities to intervene in the process of renal cell carcinoma proliferation, angiogenesis and invasion. Modulation of the CXCR3/CXCR3-ligand or the CXCR4/CXCL12 biologic axis may be potential therapeutic targets for the treatment of renal cell carcinoma. Furthermore, combination treatment with agents targeting chemokine signaling with therapies directed at angiogenesis and tumor immunity may lead to improved outcomes in this disease.

Identification of TNF-α and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array

“…BDNF upregulates MMP-9 levels and promotes its activation (Sun et al, 2006) and, therefore, was also considered for validation by ELISA. SDF-1 was suggested by previous studies as a target for renal carcinoma therapy (Reckamp et al, 2008), and increased levels of this cytokine have been shown in sunitinib-treated mice (Ebos et al, 2007). ICAM-1 levels were also checked for validation, because plasma levels of this cytokine have been associated with a response to the anti-VEGF targeting agent bevacizumab in combination with docetaxel in metastatic breast cancer (Ramaswamy et al, 2006).…”

“…SDF-1 is secreted by carcinoma-associated fibroblasts and stimulates cancer cell growth directly through the CXCR4 receptor expressed on tumour cells, and also recruits endothelial progenitor cells into tumours, thereby fostering neoangiogenesis (Orimo and Weinberg, 2006). The SDF-1/CXCR4 pathway has been suggested as a target for renal cancer therapy (Reckamp et al, 2008), and dosedependent increases in SDF-1 levels have been reported previously in normal nontumour-bearing mice treated with sunitinib in a previous study (Ebos et al, 2007), which further supports our results. BDNF is a novel angiogenic factor that upregulates MMP-2 and MMP-9 and promotes their activation (Sun et al, 2006).…”

Optimizing recent advances in metastatic renal cell carcinoma

“…The chemokine receptors CXCR3 and CXCR4 represent novel targets for therapeutic intervention. CXCR3 expression is associated with a favorable prognosis in RCC, and expression of this receptor on mononuclear cells is induced with IL-2 treatment [43]. IL-2 binds CXCR3 on Th1 cells, thereby promoting an antitumor immune response [43].…”

“…CXCR3 expression is associated with a favorable prognosis in RCC, and expression of this receptor on mononuclear cells is induced with IL-2 treatment [43]. IL-2 binds CXCR3 on Th1 cells, thereby promoting an antitumor immune response [43]. Chemokines induced by IFN, including CXCL4, CXCL9, CXCL10, and CXCL11, bind CXCR3 to elicit an antiangiogenic response and promote cell-mediated immunity [43].…”

Structure-based design of inhibitors of CXCR4.

“…CXCR4 has been demonstrated to playa critical role in angiogenesis [17] and metastasis [18] of several tumors, including basal cell carcinoma [17], thyroid cancer [18], squamous cell carcinoma [19], neuroblastoma [20], ovarian [21], melanoma [22], renal cell carcinoma [23], hepatocellular carcinoma [24], breast [25], colon [26], lung [25], pancreatic [27] and prostate cancers [25]. Chinni et al expanded on the Muller theory by demonstrating that bone metastatic prostate cancer cells express cell surface CXCR4, and the CXCR4/CXCL 12 interaction was essential to migration and bone marrow invasion [28].…”