The CXCL7/CXCR1/2 Axis Is a Key Driver in the Growth of Clear Cell Renal Cell Carcinoma

Abstract

Mutations in the von Hippel-Lindau gene upregulate expression of the central angiogenic factor VEGF, which drives abnormal angiogenesis in clear cell renal cell carcinomas (ccRCC). However, the overexpression of VEGF in these tumors was not found to correlate with overall survival. Here, we show that the proangiogenic, proinflammatory cytokine CXCL7 is an independent prognostic factor for overall survival in this setting. CXCL7 antibodies strongly reduced the growth of ccRCC tumors in nude mice. Conversely, conditional overexpression of CXCL7 accelerated ccRCC development. CXCL7 promoted cell proliferation in vivo and in vitro, in which expression of CXCL7 was induced by the central proinflammatory cytokine interleukin (IL)-1b. ccRCC cells normally secrete low amounts of CXCL7; it was more highly expressed in tumors due to high levels of IL-1b there. We found that a pharmacological inhibitor of the CXCL7 receptors CXCR1 and CXCR2 (SB225002) was sufficient to inhibit endothelial cell proliferation and ccRCC growth. Because CXCR1 and CXCR2 are present on both endothelial and ccRCC cells, their inhibition affected both the tumor vasculature and the proliferation of tumor cells. Our results highlight the CXCL7/CXCR1/CXCR2 axis as a pertinent target for the treatment of ccRCC. Cancer Res; 74(3); 873-83. Ó2013 AACR.

miR-940 Suppresses Tumor Cell Invasion and Migration via Regulation of CXCR2 in Hepatocellular Carcinoma

“…Inflammatory mediators are known to play crucial roles in tumor progression by regulating not just the immune infiltrations in tumors but also by playing the important role in invasion and metastasis [20, 21]. A number of studies have demonstrated that CXCR2 plays a pivotal role in tumor angiogenesis, proliferation, and invasion [8, 22, 23]. Up to now, however, the relationship between CXCR2 and miR-940 in HCC has been little noticed.…”

The ELR+CXCL chemokines and their receptors CXCR1/CXCR2

“…In similar experiments, we showed that commercially available CXCL7 antibodies actually arrested tumor development 5 . On the other hand, tumors obtained with cells overexpressing CXCL7 grew more rapidly 5 .…”

“…In similar experiments, we showed that commercially available CXCL7 antibodies actually arrested tumor development 5 . On the other hand, tumors obtained with cells overexpressing CXCL7 grew more rapidly 5 . However, extracts from experimental tumors contained high levels of human CXCL7 whereas the CXCL7 levels produced by the cultured cancer cell lines from which our xenograft models were derived were negligible.…”

Targeting the pro-angiogenic forms of VEGF or inhibiting their expression as anti-cancer strategies

“…We previously described that redundant pro-angiogenic factors of the ELR+CXCL cytokine family played a key role in the mechanisms of resistance to BVZ in particular CXCL8 [13]. Moreover, we have also described that another member of these family of cytokines, CXCL7 is a marker of poor prognosis for RCC [24]. The production of both cytokines was thus tested in the cells derived from the different groups of tumors [25].…”