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

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 dissemination of the disease process beyond the confines of the original radiologically identifiable tumor mass, eventually resulting in near-universal tumor recurrence and, ultimately, death. Whereas patients with Grade II tumors can survive for 7 to 15 years, a diagnosis of a Grade IV glioma, or glioblastoma multiforme (GBM), carries a median survival prognosis of approximately 9 months (17). GBM also represents the most infiltrative spectrum of this disease and is frequently associated with significant involvement of peritumoral parenchyma as evidenced by the presence of extensive T2 signal abnormalities on magnetic resonance imaging (MRI). Indeed, postmortem analyses in GBM-affected brains have demonstrated the presence of tumor cells deep in the contralateral hemisphere (15). Current therapeutic regimens do not adequately address the disseminated disease burden associated with infiltrative gliomas, and there is, therefore, an urgent need to develop novel treatment approaches to specifically target the invasive capacity of these tumors. The clinical evaluation of patients with high-grade gliomas centers on the use of T1-weighted MRI sequences obtained after the administration of a gadolinium-based contrast agent to demarcate the boundaries of what is generally considered to be the surgically targetable main tumor mass. Additionally, T2-weighted imaging is used to assess the extent of the peritumoral disease process. T2-weighted signal abnormalities surrounding the T1-weighted postgadolinium-enhancing lesion are attributable to multiple facets of a progressively disseminating disease process that is inexorably extending its effects throughout the brain. In this context, our definition of glioma-associated disseminated disease would include the presence of microscopic infiltrative disease (8), foci of tumor-induced neovascularization, and generalized vasogenic edema resulting from cytokines elaborated by invasive glioma cells. As such, the extent and intensity of T2-weighted signal abnormalities can serve as a quantifiable reflection of a disseminated neoplastic disease process in the brain. Fundamental to the objective of developing effective translational therapies for this disease are the requirements for a better understanding of the biological mechanisms that govern glioma cell dispersal. Concurrently, it is critical to develop clinical imaging tools to link the presence and activity of specific biological mechanisms that drive tumor invasion and angiogenesis with an evaluation of the extent of neoplastic disease in patients with high-grade gliomas. In this context, we previously characterized the cell surface chemokine receptor CXCR4 as an important mediator of glioma cell invasiveness in vitro and in vivo (5), whereas others have reported its role in GBM neovascularization (1). In this report, we now detail an extensive analysis of CXCR4 expression in a large set of human glioma tissue samples and report a strong correlation between increasing histological grade and CXCR4 expression levels. Furthermore, we report a novel association within GBM between CXCR4 expression levels and an increased extent and intensity of preoperative T2-weighted peritumoral MRI signal abnormalities. In conjunction with our earlier report detailing the mechanistic role of CXCR4 in mediating glioma cell dispersal, these findings underscore the clinical relevance of CXCR4 based on its association with increasing invasive tumor grade and imaging-related evidence of a more disseminated disease process in the brain. Our study indicates that, in addition to further supporting the previously described roles for CXCR4 as a mediator of invasion and neovascularization, tumor CXCR4 expression levels can be used to segregate patient sets into distinct groups based on evidence of extended peritumoral disease process on T2-weighted MRI. This provides a valuable link between a routinely used clinical evaluation tool and a signaling mechanism that governs the biological aggressiveness of these tumors.