Abstract 5211: CXCR7 is a functional receptor in renal cancer cell lines

Abstract

Abstract The CXCR7 chemokine receptor is a recently deorphanized receptor for the chemokines CXCL12 (SDF-1) and CXCL11 (I-TAC) with a transduction pathway still not defined. In cancer, high CXCR7 expression was described on breast, lung, prostatic and colon cancer. In non small cell lung cancer and in pancreatic adenocarcinoma, concomitant CXCR7 and CXCR4 expression correlated with metastatic recurrence and short disease free survival. We previously demonstrated that in renal cell carcinoma (RCC) CXCR4 and CXCR7 overexpression correlates with prognosis. Aim of the study was to investigate the function of the CXCR4-CXCR7-CXCL12 axis in human renal cancer cells. To this aim CXCR4 and CXCR7 expression was evaluated in human RCC cell lines (ACHN, CAKI-S, UO31, SN12C, UOK121, UOK143, A498, TK10, 786-O) through Real Time PCR, Western blot and flow cytometry. Further studies on the possible CXCR4-CXCL12-CXCR7 function were conducted in SN12C, A498 and 786-O (cell proliferation, migration and signal transduction CXCL12-induced). In human renal cancer cells (SN12C, 786-O and A498) nor CXCL12 neither specific anti-CXCR4 (12G5 clone) and CXCR7 (11G8 clone) affected cell proliferation. Next the evaluation of migration was conducted. In SN12C and 786-O CXCL12 migration was partially inhibited by AMD3100 (a CXCR4 inhibitor) and completely inhibited by anti-CXCR4 (12G5 clone) and anti-CXCR7 (11G8 clone) antibodies. Interestingly, SN12C and 786-O cells treatment with CCX733 and CCX771, small compounds specifically binding the CXCR7 receptor, induced a dramatic increase of CXCL12-induced migration. In A498 cells, high CXCR4 and CXCR7 expressing cell lines, CXCL12 induced migration was inhibited by AMD3100 and anti-CXCR4 and anti-CXCR7 antibodies, while treatment with CCX771 and CCX733 completely inhibited migration. CXCL12 induced p-AKT was also evaluated in A498, 786-O and SN12C cells. In A498, 786-O and SN12C cells CXCL12 induced p-AKT induction; the induction was partially inhibited by AMD3100, anti-CXCR4 (12G5 clone) and CXCR7 (11G8 clone) antibodies, while was enhanced by the CCX733 and CCX771 administration. To shed further insight into the CXCR7 transduction pathway CXCR4 and CXCR7 were alternatively silenced in SN12C and A498 cell lines. SN12Csi CXCR4 were not able to migrate toward CXCL12 but still migrated toward CXCL12 in the presence of CCX733 and CCX771 small molecules. On the contrary, SN12Csi CXCR7 migration was unaffected by CXC771 and CCX733 treatment. Results on A498 are comingTaken together the results suggest that CXCR7 modulate CXCR4 function in human renal cancer cells being a new possible diagnostic and therapeutic target Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5211.