title: 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.
authors.affiliation: Laboratory of Tumor Biology and Genetics, Neurosurgery Department, University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Desbaillets
authors.forename: A C
authors.initials: AC
authors.lastname: Diserens
authors.forename: N
authors.initials: N
authors.lastname: Tribolet
authors.forename: M F
authors.initials: MF
authors.lastname: Hamou
authors.forename: E G
authors.initials: EG
authors.lastname: Van Meir
mesh_terms: D000693:Anaerobiosis; D015703:Antigens, CD / Q000096:biosynthesis; D015152:Blotting, Northern; D015687:Cell Hypoxia / Q000276:immunology; D002634:Chemotaxis, Leukocyte; D018450:Disease Progression; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D017403:In Situ Hybridization; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D018919:Neovascularization, Physiologic / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis; D023062:Receptors, Interleukin-8A; D018874:Spheroids, Cellular; D015854:Up-Regulation
chemical_list: D015703:Antigens, CD; D016209:Interleukin-8; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A