IL-17 Enhances the Net Angiogenic Activity and In Vivo Growth of Human Non-Small Cell Lung Cancer in SCID Mice through Promoting CXCR-2-Dependent Angiogenesis

Abstract

In this study, we examined the biological action of IL-17 on human non-small cell lung cancer (NSCLC). Although IL-17 had no direct effect on the in vitro growth rate of NSCLC, IL-17 selectively augmented the secretion of an array of angiogenic CXC chemokines, including CXCL1, CXCL5, CXCL6, and CXCL8 but not angiostatic chemokines, by three different NSCLC lines. Endothelial cell chemotactic activity (as a measure of net angiogenic potential) was increased in response to conditioned medium from NSCLC stimulated with IL-17 compared with those from unstimulated NSCLC. Enhanced chemotactic activity was suppressed by neutralizing mAb(s) to CXCL1, CXCL5, and CXCL8 or to CXCR-2 but not to vascular endothelial growth factor-A. Transfection with IL-17 into NSCLC had no effect on the in vitro growth, whereas IL-17 transfectants grew more rapidly compared with controls when transplanted in SCID mice. This IL-17-elicited enhancement of NSCLC growth was associated with increased tumor vascularity. Moreover, treatment with anti-mouse CXCR-2-neutralizing Ab significantly attenuated the growth of both neomycin phosphotransferase gene-transfected and IL-17-transfected NSCLC tumors in SCID mice. A potential role for IL-17 in modulation of the human NSCLC phenotype was supported by the findings that, in primary NSCLC tissues, IL-17 expression was frequently detected in accumulating and infiltrating inflammatory cells and that high levels of IL-17 expression were associated with increased tumor vascularity. These results demonstrate that IL-17 increases the net angiogenic activity and in vivo growth of NSCLC via promoting CXCR-2-dependent angiogenesis and suggest that targeting CXCR-2 signaling may be a novel promising strategy to treat patients with NSCLC.

Tumor‐infiltrating IL‐17‐producing γδ T cells support the progression of tumor by promoting angiogenesis

“…We have clearly demonstrated that the established tumor progression was significantly diminished in IL-17 À/À mice, due to a decrease of angiogenesis. Consistent with this finding, prior studies have shown that substantial IL-17 expression levels in human cancer tissues were correlated with increased vascularity [4,5]. Moreover, our findings are consistent with other reports that IL-17 directly influenced on the proliferation and survival of tumor cells and that IL-6-STAT3 pathway promoted tumor growth in IL-17-dependent manner [34,43].…”

“…It has been demonstrated that IL-17 is expressed in tumor microenvironments [3][4][5]. The precise role of IL-17 during tumor development, however, remains unclear.…”

“…Tumor cells promote neo-vascularization into tumor tissues through hyperproduction of angiogenic factors, which also support their own abnormal proliferation and survival [6]. It has been reported that tumor cells over-expressing IL-17 significantly promote new vessel growth into the tumor tissues [5]; however, physiological effects of IL-17 on tumor progression remain to be defined. Th17 differentiation from naïve CD4 1 T cells is regulated by TGF-b and IL-6.…”

“…Thus, the tumor microenvironment is conducive to IL-17 production. In fact, it has been shown that IL-17 is produced in human and murine tumor tissues [3][4][5]. Tumor cells promote neo-vascularization into tumor tissues through hyperproduction of angiogenic factors, which also support their own abnormal proliferation and survival [6].…”

TGF-β and tumors—an ill-fated alliance

“…In so doing, TGF-β engages IL-17 production, important in defense against extracellular bacterial pathogens, but now linked to tumorigenesis. Functionally, over-expression of IL-17 in tumor sites correlated with recruitment of phagocytes, along with increased angiogenesis [16]. Recognized for its ability to induce cytokines, chemokines, colony stimulating factors and pro-angiogenic factors in multiple cell types, IL-17 enhanced tumor vascularity was inhibitable by CXCR2 neutralization [16].…”