CXC‐chemokine/CXCR2 biological axis promotes angiogenesis in vitro and in vivo in pancreatic cancer

Abstract

Angiogenesis is essential for tumor growth and metastasis. Although ELR 1 -CXC-chemokines and their corresponding receptor, CXC-receptor 2 (CXCR2), are known mediators of angiogenesis, little is known about their role in pancreatic cancer (PaCa). The aim of our study was to determine the role of ELR 1 -CXCchemokine/CXCR2 biological axis in promoting PaCa angiogenesis. We prospectively collected secretin-stimulated exocrine pancreatic secretions (SSEPS) from normal individuals (NP) and PaCa patients. We showed that summed concentrations of ELR 1 -CXC-chemokines in SSEPS from PaCa patients were significantly higher than in those from NP (p 5 0.002). We measured ELR 1 -CXC-chemokine levels in supernatants from multiple PaCa cell lines and confirmed that BxPC-3, Colo-357 and Panc-28 had significantly higher expression compared with an immortalized human pancreatic ductal epithelial (HPDE) cell line. After confirming lack of autocrine effects of ELR 1 -CXC-chemokines on PaCa cells (due to absence of CXCR2 expression), we investigated paracrine effects of these chemokines on human umbilical vein endothelial cells (HUVEC). Both recombinant ELR 1 -CXC-chemokines and co-culturing with BxPC-3 significantly enhanced proliferation, invasion, and tube formation of HUVEC (p < 0.05). These biological effects were significantly inhibited by treatment with a neutralizing antibody against CXCR2 (anti-CXCR2 Ab) (p < 0.05). Finally, anti-CXCR2 Ab significantly reduced tumor volume (p < 0.05), Ki-67 proliferation index (p 5 0.043) and Factor VIII 1 microvessel density (p 5 0.004) in an orthotopic nude mouse PaCa model. Our results show that ELR 1 -CXC-chemokines promote PaCa tumor-associated angiogenesis through CXCR2, suggesting that CXCR2 is an anti-angiogenic target in PaCa. ' 2009 UICC

Cancer Related Inflammation and Tumor Angiogenesis

“…The results of these studies support the notion that CXCR2 mediates the angiogenic activity of ELR(+) CXC chemokines in a preclinical model of lung cancer [41]. Similar effect of ELR(+) CXC chemokines and CXCR2 on tumor-associated angiogenesis was also shown in pancreatic cancer [42]. In vitro, ELR + CXC chemokines in supernatants from multiple pancreatic cancer cell lines had significantly higher level compared with an immortalized human pancreatic ductal epithelial cell line.…”

GPCRs and cancer

“…The first described angiogenic chemokine, CXCL8/IL-8, which binds to CXCR1 and CXCR2 [78] , is secreted by a variety of normal and tumor cells exposed to pro-inflammatory cytokines like IL-1 and TNF-α [79] . CXCR2 was associated to multiple signaling pathways involved in tumorigenesis, angiogenesis, proliferation and metastasis in several malignancies, including melanoma [80] , lung [81] , pancreatic [79,82] , gastric [83] , and ovarian [57] tumors. For instance, the overexpression of CXCR2 induced an aggressive phenotype of melanoma cells consisting with an enhanced proliferation, migration and tumor growth in mice [84] .…”

A natural anti-inflammatory enone fatty acid inhibits angiogenesis by attenuating nuclear factor-κB signaling in vascular endothelial cells

“…However, in our experiments, VEGF-induced angiogenesis could be, at least in part, attributed to the activation of the NF-κB pathway. In contrast, TNF-· markedly enhanced the expression of the CXC chemokines, CXCL1/GRO-· and CXCL5/ENA-78, which have themselves been shown to have potent angiogenic activity, and to stimulate cell proliferation and tube formation in endothelial cells (27,28). A neutralizing antibody to the cognate receptor, CXCR2, has been shown to block this CXC chemokine-induced proliferation and tube formation (28).…”

“…In contrast, TNF-· markedly enhanced the expression of the CXC chemokines, CXCL1/GRO-· and CXCL5/ENA-78, which have themselves been shown to have potent angiogenic activity, and to stimulate cell proliferation and tube formation in endothelial cells (27,28). A neutralizing antibody to the cognate receptor, CXCR2, has been shown to block this CXC chemokine-induced proliferation and tube formation (28). The potent inflammatory cytokines, IL-1· and IL-1ß, also stimulate the production of CXCL1/GRO-· and CXCL5/ ENA-78, which in turn induces the recruitment and activation of neutrophils and macrophages, resulting in angiogenesis (8,10).…”

“…In addition, C10 also inhibits the TNF-·-induced production of CXCL1/GRO-· and CXCL5/ENA-78. These CXC chemokines are themselves known to have potent angiogenic activity (27,28). In addition, they are potent chemo-attractants for neutrophils and monocytes/macrophages, and they recruit these cells to inflammatory foci and tumors, so that the activated neutrophils and macrophages also support angiogenesis (29)(30)(31).…”