title: 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)-1β. ccRCC cells normally secrete low amounts of CXCL7; it was more highly expressed in tumors due to high levels of IL-1β 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.
authors: Authors' Affiliations: University of Nice Sophia Antipolis, UMR CNRS 7284/U INSERM 1081; Department of Anatomo Pathology, Nice University Hospital, University of Nice Sophia Antipolis; Department of Statistics, Centre Antoine Lacassagne, Nice; University Lyon 1, Centre de Recherche en Cancérologie de Lyon, UMR CNRS 5286/U INSERM 1052, Lyon, France; and Centre Scientifique de Monaco, Monaco.
authors: Renaud
authors: R
authors: Grépin
authors: Mélanie
authors: M
authors: Guyot
authors: Sandy
authors: S
authors: Giuliano
authors: Marina
authors: M
authors: Boncompagni
authors: Damien
authors: D
authors: Ambrosetti
authors: Emmanuel
authors: E
authors: Chamorey
authors: Jean-Yves
authors: JY
authors: Scoazec
authors: Sylvie
authors: S
authors: Negrier
authors: Hélène
authors: H
authors: Simonnet
authors: Gilles
authors: G
authors: Pagès
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000494:pharmacology; D011379:Prognosis; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D001620:beta-Thromboglobulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C061615:PPBP protein, human; D010671:Phenylurea Compounds; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; C112019:SB 225002; D001620:beta-Thromboglobulin