The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis.
Journal: 2005/May - Neuro-Oncology
ISSN: 1522-8517
Abstract:
Interleukin-8 (IL-8, or CXCL8), which is a chemokine with a defining CXC amino acid motif that was initially characterized for its leukocyte chemotactic activity, is now known to possess tumorigenic and proangiogenic properties as well. In human gliomas, IL-8 is expressed and secreted at high levels both in vitro and in vivo, and recent experiments suggest it is critical to glial tumor neovascularity and progression. Levels of IL-8 correlate with histologic grade in glial neoplasms, and the most malignant form, glioblastoma, shows the highest expression in pseudopalisading cells around necrosis, suggesting that hypoxia/anoxia may stimulate expression. In addition to hypoxia/anoxia stimulation, increased IL-8 in gliomas occurs in response to Fas ligation, death receptor activation, cytosolic Ca(2+), TNF-alpha, IL-1, and other cytokines and various cellular stresses. The IL-8 promoter contains binding sites for the transcription factors NF-kappaB, AP-1, and C-EBP/NF-IL-6, among others. AP-1 has been shown to mediate IL-8 upregulation by anoxia in gliomas. The potential tumor suppressor ING4 was recently shown to be a critical regulator of NF-kappaB-mediated IL-8 transcription and subsequent angiogenesis in gliomas. The IL-8 receptors that could contribute to IL-8-mediated tumorigenic and angiogenic responses include CXCR1 and CXCR2, both of which are G-protein coupled, and the Duffy antigen receptor for cytokines, which has no defined intracellular signaling capabilities. The proangiogenic activity of IL-8 occurs predominantly following binding to CXCR2, but CXCR1 appears to contribute as well through independent, small-GTPase activity. A precise definition of the mechanisms by which IL-8 exerts its proangiogenic functions requires further study for the development of effective IL-8-targeted therapies.
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Neuro Oncol 7(2): 122-133

The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis<sup><a href="#fn1-neu0702p122" rid="fn1-neu0702p122" class=" fn">1</a></sup>

Department of Pathology and Laboratory Medicine (D.J.B.) and Laboratory of Molecular Neuro-Oncology, Departments of Neurosurgery and Hematology/Oncology, and Winship Cancer Institute (A.C.B., E.G.V.M.), Emory University School of Medicine, Atlanta, GA 30322, USA
Send correspondence to Erwin G. Van Meir, Laboratory of Molecular Neuro-Oncology, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road NE, Room C-5078, Atlanta, GA 30322, USA ( ude.yrome@iemnave).
Received 2004 Nov 16; Accepted 2005 Jan 10.

Abstract

Interleukin-8 (IL-8, or CXCL8), which is a chemokine with a defining CXC amino acid motif that was initially characterized for its leukocyte chemotactic activity, is now known to possess tumorigenic and proangiogenic properties as well. In human gliomas, IL-8 is expressed and secreted at high levels both in vitro and in vivo, and recent experiments suggest it is critical to glial tumor neovascularity and progression. Levels of IL-8 correlate with histologic grade in glial neoplasms, and the most malignant form, glioblastoma, shows the highest expression in pseudopalisading cells around necrosis, suggesting that hypoxia/anoxia may stimulate expression. In addition to hypoxia/anoxia stimulation, increased IL-8 in gliomas occurs in response to Fas ligation, death receptor activation, cytosolic Ca, TNF-α, IL-1, and other cytokines and various cellular stresses. The IL-8 promoter contains binding sites for the transcription factors NF-κB, AP-1, and C-EBP/NF-IL-6, among others. AP-1 has been shown to mediate IL-8 upregulation by anoxia in gliomas. The potential tumor suppressor ING4 was recently shown to be a critical regulator of NF-κB-mediated IL-8 transcription and subsequent angiogenesis in gliomas. The IL-8 receptors that could contribute to IL-8-mediated tumorigenic and angiogenic responses include CXCR1 and CXCR2, both of which are G-protein coupled, and the Duffy antigen receptor for cytokines, which has no defined intracellular signaling capabilities. The proangiogenic activity of IL-8 occurs predominantly following binding to CXCR2, but CXCR1 appears to contribute as well through independent, small-GTPase activity. A precise definition of the mechanisms by which IL-8 exerts its proangiogenic functions requires further study for the development of effective IL-8-targeted therapies.

Abstract

Tumorigenesis is a complex, multistep process that includes cellular neoplastic transformation, resistance to apoptosis, autonomous growth signaling, emergence of a vascular supply, evasion of immunologic surveillance, and the acquisition of invasive/metastatic properties. Soluble factors in the tumoral environment—derived not only from neoplastic cells but also from stroma, inflammatory cells, and endothelial cells—are critical determinants of many of these neoplastic processes. Direct and indirect evidence strongly implicates a subset of soluble factors, the chemokines, as key regulators of tumorigenesis (Balkwill, 2004Vicari and Caux, 2002). One of these, interleukin-8 (IL-8,3 or CXCL8), is best known for its leukocyte chemotactic properties and associated role in inflammatory and infectious diseases (Harada et al., 1994), although its tumorigenic and proangiogenic activities that were first suggested in the early 1990s are now widely accepted (Xie, 2001). This review focuses on our current knowledge of IL-8 and its receptors, with an emphasis on the role of IL-8 signaling in gliomagenesis and angiogenesis.

Footnotes

Supported in part by the U.S. Public Health Service National Institutes of Health (NIH) grants CA-86335 (E.G.V.M.) and NS-42934 (D.J.B.), the Musella Foundation (E.G.V.M.), and the Pediatric Brain Tumor Foundation of the U.S. (E.G.V.M.).

Abbreviations used are as follows: AU, adenosine and uridine; CSF, cerebrospinal fluid; CXCR, CXC chemokine receptor; DARC, Duffy antigen receptor for cytokines; DR, death receptor; EGFR, epidermal growth factor receptor; ELF, Glu-Leu-Arg; ENA, epithelial-cell-derived neutrophil-activating protein; ERK 1/2, extracellular signal–regulated kinase 1 and 2; GBM, glioblastoma; GCP, granulocyte chemotactic protein; GRO, growth-regulated oncogene; HIF, hypoxia-inducible factor; HIMEC, human intestinal microvasculature endothelial cells; HMEC, human microvascular endothelial cell; HUVEC, human umbilical vein endothelial cells; IL-8, interleukin-8; MAP, mitogen-activated protein; MEKK1, MAP kinase kinase kinase 1; Mig, monokine induced by γ-interferon; MKK, MAP kinase kinase; MMP, matrix metalloproteinase; NIK, NF-κB-inducing kinase; PI-3-K, phosphoinositide 3 kinase; TRAIL, tumor necrosis factor–related, apoptosis-inducing ligand; VEGF, vascular endothelial growth factor.

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