AI-07 * GLIOBLASTOMA SUBTYPES DO NOT EXPLOIT DIFFERENTIAL ANGIOGENIC SIGNALING PATHWAYS NOR ARE THE VESSELS FUNCTIONALLY DIFFERENT

Abstract

Glioblastoma is the most aggressive type of primary brain tumor in adults with dismal survival and for which novel therapeutic regimens are warranted. Over the last decade molecular subtypes of glioblastoma related to clinical outcome and response to therapy have been described. Of these subtypes, especially the mesenchymal type has been ascribed high angiogenic activity. The feasibility and efficacy of therapy targeted at the vascular compartment is now studied widely, but in clinical trials evaluating anti-angiogenic therapy molecular subtype analyses were not included. In this study we analyzed the acitivation of angiogenic signaling pathways and the vascular status of molecular subtypes of glioblastoma. Tissue samples of primary glioblastomas of proneural, classical and mesenchymal subtypes, 10 samples per subclasses, were utilized for all experiments. The activation of angiogenic signaling pathways, including the VEGF pathway, the Angiopoietin/TIE-2 pathway, and DLL4-Notch signaling, was determined through quantitative PCR analyses by assessing targets from these pathways. These analyses revealed that no specific pathway activation confined to one of the subtypes could be observed and none of the addressed targets was expressed differentially between the subtypes. Morphometric analyses were performed to determine the vascular status of the molecular subtypes. These analyses were confined to the vital tissue, which was itself subdivided into hypoxic and normoxic regions. Mesenchymal tumors, in comparison to proneural tumors, had a relatively larger hypoxic area and the vessels were larger as was determined by volumetric measurements and Chalkley grid overlays. The number and maturation of vessels, assessed by manual counting, α-smooth muscle actin and Collagen IV staining, was found not to vary between the subtypes. This study provides evidence that mesenchymal tumors have larger vessels, but targets suitable for subtype-specific anti-angiogenic treatment were not discovered.