Cxcr4 Expression Is Elevated in Glioblastoma Multiforme and Correlates With an Increase in Intensity and Extent of Peritumoral T2-Weighted Magnetic Resonance Imaging Signal Abnormalities

Abstract

Objective-With the objective of investigating the utility of CXCR4, a chemokine receptor known to mediate glioma cell invasiveness, as a molecular marker for peritumoral disease extent in highgrade gliomas, we sought to characterize the expression profile of CXCR4 in a large panel of tumor samples and determine whether CXCR4 expression levels within glioblastoma multiforme might correlate with radiological evidence of a more extensive disease process.Methods-Freshly resected tumor tissue samples were processed for immunohistochemical and quantitative polymerase chain reaction analyses to identify and quantify expression levels of CXCR4 and its corresponding ligand CXCL12. T1 postcontrast and T2-weighted magnetic resonance imaging brain scans were used to generate voxel signal intensity histograms that were quantitatively analyzed to determine the extent and intensity of peritumoral signal abnormality as a marker of disseminated disease in the brain. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptResults-CXCR4 expression was markedly elevated in Grade III and IV tumors compared with Grade II gliomas. Significantly, when patients with glioblastoma multiforme were segregated into two groups based on CXCR4 expression level, we observed a statistically significant increase in the intensity and extent of peritumoral magnetic resonance imaging signal abnormalities associated with CXCR4 high-expressing gliomas.Conclusion-Our data confirm that high-grade gliomas robustly express CXCR4 and demonstrate a correlative relationship between expression levels of the CXCR4 receptor and the magnetic resonance imaging-based finding of a diffuse and more extensive disease process in the brain. CXCR4 expression status may, therefore, prove useful as a marker of disseminated disease in patients with glioblastoma multiforme. KeywordsBrain tumor; CXCR4; Glioma Gliomas are the most common type of primary brain tumor and, according to the World Health Organization convention, are divided into four clinical grades (I-IV) on the basis of tumor histopathology (11). Grade I tumors represent a distinct subset of neoplasms occurring predominantly in children and young adults and are characterized as relatively benign lesions with well-demarcated margins and lending themselves to surgical cure. In contrast to this, Grades II, III, and IV gliomas are generally tumors of adulthood and reflect a spectrum of increasingly infiltrative and aggressive disease. These tumors have poorly defined margins and invade directly adjacent brain parenchyma, thereby precluding complete surgical resection. Despite recent advances in adjuvant radio-and chemotherapeutic regimens, current clinical treatment protocols fail to eliminate residual infiltrative tumor foci in their entirety. Additionally, invasive nests of tumor cells are associated with the initiation of neovascular angiogenesis and disruption of the blood-brain barrier via the release of vasomodulatory cytokines. Taken together, these factors contribute to a rapid disse...

The Chemokine Receptor CXCR7 Is Highly Expressed in Human Glioma Cells and Mediates Antiapoptotic Effects

“…CXCR4 has been originally described as a major widespread receptor on glioma cells (3,4), and its occurrence and localization were addressed in several previous studies. WHO grade 3 and 4 glial tumors robustly express CXCR4, and the expression levels correlate with the magnetic resonance imaging-based finding of a diffuse and more extensive disease process in the brain (28). Whereas CXCL12 is often produced in the pseudopalisading cells and the proliferating microvessels (29), CXCR4 expression is found on tumor endothelial and tumor cells, often in areas of necrosis and angiogenesis (3,29); probably also due to CXCR4 induction by hypoxia (29).…”

Expression of Chemokines and Chemokine Receptors in Brain Tumor Tissue Derived Cells

“…Human gliomas and astrocytomas produce several chemokines and receptors such as SDF-1, CXCR4, MCP-1, IL-8, IP-10, I-TAC and CXCL16 (Ludwig et al, 2005;Maru et al, 2008;Zhou et al, 2002). CXCR4 is expressed in areas of angiogenesis and in higher grades of gliomas which is associated with much progression of disease in the brain (Rempel et al, 2000;Stevenson et al, 2008;Komatani et al, 2009). Moreover, expression of chemokines and chemokine receptors would be of huge importance in meningiomas.…”

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