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.
Upregulation of Interleukin 8 by Oxygen-deprived Cells in Glioblastoma Suggests a Role in Leukocyte Activation, Chemotaxis, and Angiogenesis
Address correspondence to Erwin G. Van Meir, Laboratory of Tumor Biology and Genetics, Neurosurgery Department, University Hospital (CHUV), 1011 Lausanne, Switzerland. Phone: +41-21-314-2582; FAX: +41-21-314-2587; E-mail: [email protected]
Abbreviations used in this paper: DARC, Duffy antigen receptor for chemokines; GFAP, glial fibrillary acidic protein; mRNA, messenger RNA; RT, reverse transcription; VEGF, vascular endothelial growth factor.
Isabelle Desbaillets, Annie-Claire Diserens, Nicolas de Tribolet, Marie-France Hamou, Erwin G. Van Meir; Upregulation of Interleukin 8 by Oxygen-deprived Cells in Glioblastoma Suggests a Role in Leukocyte Activation, Chemotaxis, and Angiogenesis . J Exp Med 20 October 1997; 186 (8): 1201–1212. doi: https://doi.org/10.1084/jem.186.8.1201
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