Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0360.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/1994; 179(5):1409-15.
Source: PubMed


We investigated the role of interleukin 8 (IL-8) in mediating angiogenesis in human bronchogenic carcinoma. Increased quantities of IL-8 were detected in tumor tissue as compared with normal lung tissue. Immunohistochemical staining of tumors revealed primary localization of IL-8 to individual tumor cells and demonstrated the capacity of tumor to elaborate IL-8. Functional studies that used tissue homogenates of tumors demonstrated the induction of both in vitro endothelial cell chemotaxis and in vivo corneal neovascularization. It is important to note that the addition of neutralizing antisera to IL-8 to these assays resulted in the marked and specific attenuation of these responses. Our observations definitively establish IL-8 as a primary mediator of angiogenesis in bronchogenic carcinoma and offer a potential target for immunotherapies against solid malignancies.

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    • "Interleukin-8 (IL-8) is an inflammatory cytokine found aberrantly elevated in peritoneal fluid from women with endometriosis and originally identified as an immune cell-derived angiogenic factor (Koch et al., 1992; Smith et al., 1994; Ryan et al., 1995; Arici et al., 1996). Induction of IL-8 is controlled by various physiological stimulations, such as inflammation and hypoxia, two important factors involved in the development of endometriosis. "
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    ABSTRACT: STUDY QUESTION How does hypoxia-mediated down-regulation of dual specificity phosphatase-2 (DUSP2) promote endometriotic lesion development?SUMMARY ANSWER Inhibition of DUSP2 by hypoxia enhances endometriotic lesion growth via promoting interleukin-8 (IL-8)-dependent angiogenesis.WHAT IS KNOWN ALREADY Angiogenesis is a prerequisite for the development of endometriosis. DUSP2 is down-regulated in endometriotic stromal cells in a hypoxia inducible factor-1α-dependent manner. Down-regulation of DUSP2 contributes to the pathological process of endometriosis.STUDY DESIGN, SIZE, DURATION A laboratory study recruiting 20 patients of reproductive age with endometriosis and normal menstrual cycles, and an autoimplant-induced mouse model of endometriosis using 13 mice in a 28-day treatment.PARTICIPANTS/MATERIALS, SETTING, METHODS IL-8 mRNA levels were assayed in endometrial stromal cells maintained in normoxic or hypoxic (1% O2) conditions, with or without DUSP2 knockdown. Promoter activity and chromatin immunoprecipitation (ChIP) assays were conducted to characterize the regulation of IL-8 by DUSP2. Conditioned media from cells maintained in normoxic or hypoxic conditions, and cells with/without DUSP2 knockdown were collected to investigate the angiogenic capacity using an in vitro tube formation assay. Reparixin, an IL-8 receptor blocker, was administered to investigate the role of IL-8 in hypoxia-mediated angiogenesis and the development of endometriotic-like lesions in an autotransplanted mouse model.MAIN RESULTS AND THE ROLE OF CHANCE IL-8 mRNA was increased by both hypoxia and DUSP2 knockdown in endometrial stromal cells in an extracellular signal-regulated protein kinase-dependent manner (P < 0.05 versus control). Promoter activity and ChIP assays demonstrated that expression of IL-8 was regulated by CCAAT/enhancer binding protein α (P < 0.05 versus control). Furthermore, conditioned media collected from hypoxia-exposed or DUSP2 knockdown endometrial stromal cells promoted tube formation, which was abolished by co-treatment with reparixin (P < 0.05 versus control). Results from the autotransplanted mouse model demonstrated that number of blood vessels and size of endometriotic-like lesions were markedly reduced in recipient mice treated with reparixin (P < 0.05 versus control).LIMITATIONS, REASONS FOR CAUTION This study was conducted in primary human cell cultures and a mouse model, therefore may not fully reflect the situation in vivo.WIDER IMPLICATIONS OF THE FINDINGS This is the first study to highlight the potential application of an IL-8 receptor blocker as a therapeutic target to treat endometriosis. This study demonstrates IL-8 as a key angiogenic factor regulated by hypoxia/DUSP2, which suggests an alternative mechanism through which hypoxia may promote angiogenesis.STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the National Science Council of Taiwan (NSC101-2314-B-006-043-MY2). The author declares that there is no conflict of interest.
    Full-text · Article · Oct 2014 · Human Reproduction
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    • "Subsequently, we reported that IL-8 expression is transcriptionally upregulated by oncogenic KRAS mutations in NSCLC (Sunaga et al, 2012). IL-8 is an essential proinflammatory mediator that is involved in cancer development and acts as an angiogenic growth factor that promotes cell proliferation and angiogenesis, thus contributing to the progression and metastasis of NSCLC (Smith et al, 1994; Arenberg et al, 1996; Wang et al, 1996; Yatsunami et al, 1997; Zhu et al, 2004; Boldrini et al, 2005; Luppi et al, 2007). IL-8 has also been implicated in the epithelial–mesenchymal transition and cancer cell stemness during tumour progression (Palena et al, 2012). "
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    Full-text · Article · Feb 2014 · British Journal of Cancer
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    • "IL-8 is a potent angiogenic factor which is associated with metastasis in several cancers [11]–[14]. Study from Bequet-Romero et al. reported that conditioned media of HPV-positive cells are able to induce pro-angiogenic IL-8 expression that supports tumor growth and invasion in human umbilical vein endothelial cells [15]. They also demonstrated that IL-8 is predominantly detected in lung tumor cells [15] and the elevated IL-8 is correlated with angiogenesis, tumor progression and poor survival in non-small cell lung cancer (NSCLC) [16]–[18]. "
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    ABSTRACT: Human papillomavirus (HPV) infection is associated with non-smoking female lung cancer. Our previous report demonstrated that HPV 16 promotes lung tumor cell progression by up-regulating interleukin-17 (IL-17). IL-17 and its downstream signaling mediator, interleukin-8 (IL-8), have been implicated to modulate a variety of pro-angiogenic factors and play important roles in tumor angiogenesis and metastasis. Accordingly, we hypothesized that HPV infection may potentiate tumorigenic and metastatic characteristics of the infected cells through IL-8. The goal of the present study was to determine whether HPV infection in lung adenocarcinoma cells can promote the expression of IL-8 and metalloproteinases (MMPs) to make the transformed cells equipped with angiogenic and metastatic characteristics. The expression of IL-8 and MMPs in HPV 16 E6-transfected H1299 cells was analyzed to examine the hypothesis. HPV 16 E6 up-regulates pro-angiogenic MMP-2 and MMP-9 through inducing IL-8 expression in lung cancer cells. The results indicate that, in addition to cell proliferation-related machinery, HPV infection promotes the expression and activities of angiogenic and metastatic molecules in lung adenocarcinoma cells. The cytokines induced by HPV infection may work together to confer the malignant and tumorigenic potentials on the infected cells by promoting machineries of growth, angiogenic and metastatic characteristics.
    Preview · Article · Jun 2013 · PLoS ONE
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