J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/10/1201/12 $2.00
Volume 186, Number 8, October 20, 1997 1201-1212

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

By Isabelle Desbaillets, Annie-Claire Diserens, Nicolas de Tribolet, Marie-France Hamou, and Erwin G.  Van Meir

From the Laboratory of Tumor Biology and Genetics, Neurosurgery Department, University Hospital (CHUV), 1011 Lausanne, Switzerland

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Kaur, B., Cork, S. M., Sandberg, E. M., Devi, N. S., Zhang, Z., Klenotic, P. A., Febbraio, M., Shim, H., Mao, H., Tucker-Burden, C., Silverstein, R. L., Brat, D. J., Olson, J. J., Van Meir, E. G. (2009). Vasculostatin Inhibits Intracranial Glioma Growth and Negatively Regulates In vivo Angiogenesis through a CD36-Dependent Mechanism. Cancer Res. 69: 1212-1220 [Abstract] [Full Text]  
• Goczalik, I., Ulbricht, E., Hollborn, M., Raap, M., Uhlmann, S., Weick, M., Pannicke, T., Wiedemann, P., Bringmann, A., Reichenbach, A., Francke, M. (2008). Expression of CXCL8, CXCR1, and CXCR2 in Neurons and Glial Cells of the Human and Rabbit Retina. IOVS 49: 4578-4589 [Abstract] [Full Text]  
• Meyuhas, R., Pikarsky, E., Tavor, E., Klar, A., Abramovitch, R., Hochman, J., Lago, T. G., Honigman, A. (2008). A Key Role for Cyclic AMP-Responsive Element Binding Protein in Hypoxia-Mediated Activation of the Angiogenesis Factor CCN1 (CYR61) in Tumor Cells. Mol Cancer Res 6: 1397-1409 [Abstract] [Full Text]  
• Raghuwanshi, S. K., Nasser, M. W., Chen, X., Strieter, R. M., Richardson, R. M. (2008). Depletion of {beta}-Arrestin-2 Promotes Tumor Growth and Angiogenesis in a Murine Model of Lung Cancer. J. Immunol. 180: 5699-5706 [Abstract] [Full Text]  
• Ehses, J. A., Perren, A., Eppler, E., Ribaux, P., Pospisilik, J. A., Maor-Cahn, R., Gueripel, X., Ellingsgaard, H., Schneider, M. K.J., Biollaz, G., Fontana, A., Reinecke, M., Homo-Delarche, F., Donath, M. Y. (2007). Increased Number of Islet-Associated Macrophages in Type 2 Diabetes. Diabetes 56: 2356-2370 [Abstract] [Full Text]  
• Merighi, S., Benini, A., Mirandola, P., Gessi, S., Varani, K., Simioni, C., Leung, E., Maclennan, S., Baraldi, P. G., Borea, P. A. (2007). Caffeine Inhibits Adenosine-Induced Accumulation of Hypoxia-Inducible Factor-1{alpha}, Vascular Endothelial Growth Factor, and Interleukin-8 Expression in Hypoxic Human Colon Cancer Cells. Mol. Pharmacol. 72: 395-406 [Abstract] [Full Text]  
• Lee, T. K., Poon, R. T.P., Yuen, A. P., Ling, M. T., Wang, X. H., Wong, Y. C., Guan, X. Y., Man, K., Tang, Z. Y., Fan, S. T. (2006). Regulation of Angiogenesis by Id-1 through Hypoxia-Inducible Factor-1{alpha}-Mediated Vascular Endothelial Growth Factor Up-regulation in Hepatocellular Carcinoma. Clin. Cancer Res. 12: 6910-6919 [Abstract] [Full Text]  
• Fan, J., Chen, Y., Chan, H. M., Tam, P. K. H., Ren, Y. (2005). Removing intensity effects and identifying significant genes for Affymetrix arrays in macrophage migration inhibitory factor-suppressed neuroblastoma cells. Proc. Natl. Acad. Sci. USA 102: 17751-17756 [Abstract] [Full Text]  
• Zhang, J., Sarkar, S., Yong, V.W. (2005). The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. Carcinogenesis 26: 2069-2077 [Abstract] [Full Text]  
• Zhou, Y., Zhang, J., Liu, Q., Bell, R., Muruve, D. A., Forsyth, P., Arcellana-Panlilio, M., Robbins, S., Yong, V.W. (2005). The chemokine GRO-{alpha} (CXCL1) confers increased tumorigenicity to glioma cells. Carcinogenesis 26: 2058-2068 [Abstract] [Full Text]  
• Huang, J., Yao, J. L., Zhang, L., Bourne, P. A., Quinn, A. M., di Sant'Agnese, P. A., Reeder, J. E. (2005). Differential Expression of Interleukin-8 and Its Receptors in the Neuroendocrine and Non-Neuroendocrine Compartments of Prostate Cancer. Am. J. Pathol. 166: 1807-1815 [Abstract] [Full Text]  
• Brat, D. J., Bellail, A. C., Van Meir, E. G. (2005). The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 7: 122-133 [Abstract]  
• Rong, Y., Post, D. E., Pieper, R. O., Durden, D. L., Van Meir, E. G., Brat, D. J. (2005). PTEN and Hypoxia Regulate Tissue Factor Expression and Plasma Coagulation by Glioblastoma. Cancer Res. 65: 1406-1413 [Abstract] [Full Text]  
• Xu, L., Pathak, P. S., Fukumura, D. (2004). Hypoxia-Induced Activation of p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3'-Kinase Signaling Pathways Contributes to Expression of Interleukin 8 in Human Ovarian Carcinoma Cells. Clin. Cancer Res. 10: 701-707 [Abstract] [Full Text]  
• Ren, Y., Poon, R. T.-P., Tsui, H.-T., Chen, W.-H., Li, Z., Lau, C., Yu, W.-C., Fan, S.-T. (2003). Interleukin-8 Serum Levels in Patients with Hepatocellular Carcinoma: Correlations with Clinicopathological Features and Prognosis. Clin. Cancer Res. 9: 5996-6001 [Abstract] [Full Text]  
• Nabors, L. B., Suswam, E., Huang, Y., Yang, X., Johnson, M. J., King, P. H. (2003). Tumor Necrosis Factor {alpha} Induces Angiogenic Factor Up-Regulation in Malignant Glioma Cells: A Role for RNA Stabilization and HuR. Cancer Res. 63: 4181-4187 [Abstract] [Full Text]  
• Lu, P., Nakamoto, Y., Nemoto-Sasaki, Y., Fujii, C., Wang, H., Hashii, M., Ohmoto, Y., Kaneko, S., Kobayashi, K., Mukaida, N. (2003). Potential Interaction between CCR1 and Its Ligand, CCL3, Induced by Endogenously Produced Interleukin-1 in Human Hepatomas. Am. J. Pathol. 162: 1249-1258 [Abstract] [Full Text]  
• Hor, W.-S., Huang, W.-L., Lin, Y.-S., Yang, B.-C. (2003). Cross-talk between tumor cells and neutrophils through the Fas (APO-1, CD95)/FasL system: human glioma cells enhance cell viability and stimulate cytokine production in neutrophils. J. Leukoc. Biol. 73: 363-368 [Abstract] [Full Text]  
• Dietrich, P.-Y., Walker, P. R., Saas, P. (2003). Death receptors on reactive astrocytes: A key role in the fine tuning of brain inflammation?. Neurology 60: 548-554 [Abstract] [Full Text]  
• Chen, J. J.W., Yao, P.-L., Yuan, A., Hong, T.-M., Shun, C.-T., Kuo, M.-L., Lee, Y.-C., Yang, P.-C. (2003). Up-Regulation of Tumor Interleukin-8 Expression by Infiltrating Macrophages: Its Correlation with Tumor Angiogenesis and Patient Survival in Non-Small Cell Lung Cancer. Clin. Cancer Res. 9: 729-737 [Abstract] [Full Text]  
• Zhou, Y., Larsen, P. H., Hao, C., Yong, V. W. (2002). CXCR4 Is a Major Chemokine Receptor on Glioma Cells and Mediates Their Survival. J. Biol. Chem. 277: 49481-49487 [Abstract] [Full Text]  
• Osawa, Y., Nagaki, M., Banno, Y., Brenner, D. A., Asano, T., Nozawa, Y., Moriwaki, H., Nakashima, S. (2002). Tumor Necrosis Factor Alpha-Induced Interleukin-8 Production via NF-{kappa}B and Phosphatidylinositol 3-Kinase/Akt Pathways Inhibits Cell Apoptosis in Human Hepatocytes. Infect. Immun. 70: 6294-6301 [Abstract] [Full Text]  
• Fujimoto, J., Aoki, I., Khatun, S., Toyoki, H., Tamaya, T. (2002). Clinical implications of expression of interleukin-8 related to myometrial invasion with angiogenesis in uterine endometrial cancers. Ann Oncol 13: 430-434 [Abstract] [Full Text]  
• Yuan, A., Yu, C.-J., Luh, K.-T., Kuo, S.-H., Lee, Y.-C., Yang, P.-C. (2002). Aberrant p53 Expression Correlates With Expression of Vascular Endothelial Growth Factor mRNA and Interleukin-8 mRNA and Neoangiogenesis in Non-Small-Cell Lung Cancer. JCO 20: 900-910 [Abstract] [Full Text]  
• Choi, C., Kutsch, O., Park, J., Zhou, T., Seol, D.-W., Benveniste, E. N. (2002). Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Induces Caspase-Dependent Interleukin-8 Expression and Apoptosis in Human Astroglioma Cells. Mol. Cell. Biol. 22: 724-736 [Abstract] [Full Text]  
• Choi, C., Xu, X., Oh, J.-W., Lee, S. J., Gillespie, G. Y., Park, H., Jo, H., Benveniste, E. N. (2001). Fas-induced Expression of Chemokines in Human Glioma Cells: Involvement of Extracellular Signal-regulated Kinase 1/2 and p38 Mitogen-activated Protein Kinase. Cancer Res. 61: 3084-3091 [Abstract] [Full Text]  
• Nabors, L. B., Gillespie, G. Y., Harkins, L., King, P. H. (2001). HuR, a RNA Stability Factor, Is Expressed in Malignant Brain Tumors and Binds to Adenine- and Uridine-rich Elements within the 3' Untranslated Regions of Cytokine and Angiogenic Factor mRNAs. Cancer Res. 61: 2154-2161 [Abstract] [Full Text]  
• Brat, D. J., Van Meir, E. G. (2001). Glomeruloid Microvascular Proliferation Orchestrated by VPF/VEGF : A New World of Angiogenesis Research. Am. J. Pathol. 158: 789-796 [Full Text]  
• Haqqani, A. S., Sandhu, J. K., Birnboim, H.C. (2001). Constitutive expression of interleukin-8 by Mutatect cells markedly affects their tumor biology. Carcinogenesis 22: 243-250 [Abstract] [Full Text]  
• YUAN, A., YANG, P.-C., YU, C.-J., CHEN, W.-J., LIN, F.-Y., KUO, S.-H., LUH, K.-T. (2000). Interleukin-8 Messenger Ribonucleic Acid Expression Correlates with Tumor Progression, Tumor Angiogenesis, Patient Survival, and Timing of Relapse in Non-Small-Cell Lung Cancer. Am. J. Respir. Crit. Care Med. 162: 1957-1963 [Abstract] [Full Text]  
• Persidsky, Y., Zheng, J., Miller, D., Gendelman, H. E. (2000). Mononuclear phagocytes mediate blood-brain barrier compromise and neuronal injury during HIV-1-associated dementia. J. Leukoc. Biol. 68: 413-422 [Abstract] [Full Text]  
• Tenan, M., Fulci, G., Albertoni, M., Diserens, A.-C., Hamou, M.-F., El Atifi-Borel, M., Feige, J.-J., Pepper, M. S., Van Meir, E. G. (2000). Thrombospondin-1 Is Downregulated by Anoxia and Suppresses Tumorigenicity of Human Glioblastoma Cells. JEM 191: 1789-1798 [Abstract] [Full Text]  
• Fujimoto, J., Sakaguchi, H., Aoki, I., Tamaya, T. (2000). Clinical Implications of Expression of Interleukin 8 Related to Angiogenesis in Uterine Cervical Cancers. Cancer Res. 60: 2632-2635 [Abstract] [Full Text]  
• Kessler, R., Hamou, M.-F., Albertoni, M., de Tribolet, N., Arand, M., Van Meir, E. G. (2000). Identification of the Putative Brain Tumor Antigen BF7/GE2 as the (De)Toxifying Enzyme Microsomal Epoxide Hydrolase. Cancer Res. 60: 1403-1409 [Abstract] [Full Text]  
• Sandhu, J. K., Privora, H. F., Wenckebach, G., Birnboim, H. C. (2000). Neutrophils, Nitric Oxide Synthase, and Mutations in the Mutatect Murine Tumor Model. Am. J. Pathol. 156: 509-518 [Abstract] [Full Text]  
• Fasciani, A., D'Ambrogio, G., Bocci, G., Monti, M., Genazzani, A.R., Artini, P.G. (2000). High concentrations of the vascular endothelial growth factor and interleukin-8 in ovarian endometriomata. Mol Hum Reprod 6: 50-54 [Abstract] [Full Text]  
• Shi, Q., Abbruzzese, J. L., Huang, S., Fidler, I. J., Xiong, Q., Xie, K. (1999). Constitutive and Inducible Interleukin 8 Expression by Hypoxia and Acidosis Renders Human Pancreatic Cancer Cells More Tumorigenic and Metastatic. Clin. Cancer Res. 5: 3711-3721 [Abstract] [Full Text]  
• Saas, P., Boucraut, J., Quiquerez, A.-L., Schnuriger, V., Perrin, G., Desplat-Jego, S., Bernard, D., Walker, P. R., Dietrich, P.-Y. (1999). CD95 (Fas/Apo-1) as a Receptor Governing Astrocyte Apoptotic or Inflammatory Responses: A Key Role in Brain Inflammation?. J. Immunol. 162: 2326-2333 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS