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

Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Sendai, Japan.
The Journal of Immunology (Impact Factor: 4.92). 12/2005; 175(9):6177-89. DOI: 10.4049/jimmunol.175.9.6177
Source: PubMed

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.

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Available from: Muneo Numasaki, Sep 26, 2015
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    • "However, the role of IL-17 in tumor immunity remains undefined. Functionally, overexpression of IL-17 in tumor cell lines promotes angiogenesis and tumor growth when the tumors are implanted in immune-compromised mice [85]. Intranasal treatment of mice with a neutralizing anti-IL-17A antibody in experimental lung adenocarcinoma caused a significant reduction of tumor growth as compared to control treated mice [32]. "
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    ABSTRACT: Pathogenic mechanisms underlying the development of lung cancer are very complex and not yet entirely clarified. T lymphocytes and their immune-regulatory cytokines play a pivotal role in controlling tumor growth and metastasis. Following activation by unique cytokines, CD4+ T helper cells differentiate into Th1, Th2, Th17, and regulatory T cells (Tregs). Traditionally, research in lung cancer immunity has focused almost exclusively on Th1/Th2 cell balance. Recently, Th17 cells and Tregs represent an intriguing issue to be addressed in lung cancer pathogenesis. Tregs play an important role in the preservation of self-tolerance and modulation of overall immune responses against tumor cells. Th17 cells directly or via other proinflammatory cytokines modulate antitumor immune responses. Notably, there is a close relation between Tregs and Th17 cells. However, the possible interaction between these subsets in lung cancer remains to be elucidated. In this setting, targeting Treg/Th17 balance for therapeutic purposes may represent a useful tool for lung cancer treatment in the future. The purpose of this review is to discuss recent findings of the role of these novel populations in lung cancer immunity and to highlight the pleiotropic effects of these subsets on the development and regulation of lung cancer.
    Research Journal of Immunology 04/2014; 2014:730380. DOI:10.1155/2014/730380
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    • "Tartour et al. [39] injected nude mice with human cervical tumor cells transfected with human cDNA encoding IL-17 and found that they grew more quickly than parental tumors. Numasaki et al. [38] demonstrated that human nonsmall cell lung cancer transfected with human IL-17 grew faster in severe combined immunodeficiency (SCID) mice than did control non-small cell lung cancer cells. "
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    ABSTRACT: CD4+ T helper (Th) cells play an important role in modulating immune responses. Th17 cells are a newly established Th subpopulation. Th17 cells differentiate in the presence of TGF-β and IL-6 in mice or IL-1β and IL-6 in humans, depending on the transcription factor RORγt. IL-23 stabilizes the Th17 cells phenotype and helps Th17 cells acquire effector functions. Th17 secretes IL-17, IL-21, and IL-22, which play significant role in the immune response against viruses, extracellular bacteria and fungi, as well as in the pathogenesis of inflammatory diseases. The systemic and local activity of IL-17 and Th17 seems to be an important part of development of autoimmune reaction. Th17 cell subpopulation has been described in many types of cancer, including gastric cancer, melanoma, breast cancer, and ovarian cancer, but it remains unclear whether Th17 cells promote or inhibit tumor progression and the mechanism of their involvement in tumor immunity is unknown. This review summarizes the current knowledge on the role of Th17 cells in tumor immunity.
    Acta haematologica Polonica 04/2014; 45(2). DOI:10.1016/j.achaem.2014.04.017
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    • "Thus, we speculate that the production of IL-17 may mediate the potential roles of Tc17 cells in cancer progression. However, the forced ectopic overexpression of IL-17 in tumor cells demonstrated conflicting effects on tumor growth: tumor inhibiting [35], [36] versus tumor promoting [21], [37]. Notably, Nam et al. [31] reported that IL-17 suppressed apoptosis in several tumor cell lines in vitro, and knockdown of the IL-17 receptor in 4T1 mouse mammary cancer cells enhanced apoptosis and decreased tumor growth in vivo. "
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    ABSTRACT: The existence of Tc17 cells was recently shown in several types of infectious and autoimmune diseases, but their distribution and functions in uterine cervical cancer (UCC) have not been fully elucidated. The frequency of Tc17 cells in peripheral blood samples obtained from UCC patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls was determined by flow cytometry. Besides, the prevalence of Tc17 cells and their relationships to Th17 cells and Foxp3-expressing T cells as well as microvessels in tissue samples of the patients were assessed by immunohistochemistry staining. Compared to controls, patients with UCC or CIN had a higher proportion of Tc17 cells in both peripheral blood and cervical tissues, but the level of Tc17 cells in UCC tissues was significantly higher than that in CIN tissues. Besides, the increased level of Tc17 in UCC patients was associated with the status of pelvic lymph node metastases and increased microvessel density. Finally, significant correlations of infiltration between Tc17 cells and Th17 cells or Foxp3-expressing T cells were observed in UCC and CIN tissues. This study indicates that Tc17 cell infiltration in cervical cancers is associated with cancer progression accompanied by increased infiltrations of Th17 cells and regulatory T cells as well as promoted tumor vasculogenesis.
    PLoS ONE 02/2014; 9(2):e86812. DOI:10.1371/journal.pone.0086812 · 3.23 Impact Factor
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