Upregulation of Interleukin 8 by Oxygen-deprived Cells in Glioblastoma Suggests a Role in Leukocyte Activation, Chemotaxis, and Angiogenesis

Abstract

Leukocyte infiltration and necrosis are two biological phenomena associated with the development of neovascularization during the malignant progression of human astrocytoma. Here, we demonstrate expression of interleukin (IL)-8, a cytokine with chemotactic and angiogenic properties, and of IL-8–binding receptors in astrocytoma. IL-8 expression is first observed in low grade astrocytoma in perivascular tumor areas expressing inflammatory cytokines. In glioblastoma, it further localizes to oxygen-deprived cells surrounding necrosis. Hypoxic/anoxic insults on glioblastoma cells in vitro using anaerobic chamber systems or within spheroids developing central necrosis induced an increase in IL-8 messenger RNA (mRNA) and protein expression. mRNA for IL-8–binding chemokine receptors CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC) were found in all astrocytoma grades by reverse transcription/PCR analysis. In situ hybridization and immunohistochemistry localized DARC expression on normal brain and tumor microvascular cells and CXCR1 and CXCR2 expression to infiltrating leukocytes. These results support a model where IL-8 expression is initiated early in astrocytoma development through induction by inflammatory stimuli and later in tumor progression increases due to reduced microenvironmental oxygen pressure. Augmented IL-8 would directly and/or indirectly promote angiogenesis by binding to DARC and by inducing leukocyte infiltration and activation by binding to CXCR1 and CXCR2.

Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma

“…However, the role of MIF in angiogenesis involving tumor and endothelial cells is less well understood. IL-8 has been identified as an angiogenesis-regulating molecule that induces angiogenesis (Koch et al, 1992;Desbaillets et al, 1997). The expression of IL-8 has been found in various human cancers (Xie, 2001).…”

Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential

“…We suspect that regulator DARC may also participate angiogenesis in breast cancer. Although some studies had shown that DARC is expressed in several kinds of tumors, including erythroleukemia Inhibition of breast cancer growth and metastasis by DARC J Wang et al , glioblastoma (Desbaillets et al, 1997) and hemangiosarcomas (Tang et al, 1998), the function of DARC in tumors remains unknown. In order to investigate the effects and the mechanisms of DARC in breast tumor, we established DARC overexpressing MDA-MB-435HM and MDA-MB-231 cell lines by stable transfection.…”

Neutrophils, Nitric Oxide Synthase, and Mutations in the Mutatect Murine Tumor Model

“…In an study of human glioblastoma, Desbaillets et al have observed that IL-8 expression was found in hypoxic tumor cells surrounding areas of necrosis. 33 In gastric carcinomas, the presence of IL-8 was correlated with microvessel count. 34 A model to depict some of the events that may be occurring in the complex tumor microenironment is presented in Figure 5.…”

“…For example, interleukin-8 (IL-8), a potent chemoattractant for neutrophils of the C-X-C type, 32 has been shown in glioblastoma. 33 IL-8 has also been identified in human gastric, colorectal and bronchioloalveolar carcinomas 34 -36 and in B-cell chronic lymphocytic leukemia. 37 High expression of several C-C chemokines, in particular, monocyte chemoattractant protein-1, was identified in epithelial ovarian cancers where CD68ϩ macrophages and CD8ϩ/CD45ROϩ T cells were the primary infiltrating cells.…”