Longitudinal Expression Analysis of αv Integrins in Human Gliomas Reveals Upregulation of Integrin αvβ3 as a Negative Prognostic Factor

Integrin inhibitors targeting alpha v series integrins are being tested for their therapeutic potential in patients with brain tumors, but pathologic studies have been limited by lack of antibodies suitable for immunohistochemistry (IHC) on formalin-fixed, paraffin-embedded specimens. We compared the expression of alpha v integrins by IHC in brain tumor and normal human brain samples with gene expression data in a public database using new rabbit monoclonal antibodies against alpha v beta 3, alpha v beta 5, alpha v beta 6, and alpha v beta 8 complexes using both manual and automated microscopy analyses. Glial tumors usually shared an alpha v beta 3-positive/alpha v beta 5-positive/alpha v beta 8-positive/alpha v beta 6-negative phenotype. In 94 WHO (World Health Organization) grade II astrocytomas, 85 anaplastic astrocytomas WHO grade III, and 324 glioblastomas from archival sources, expression of integrins generally increased with grade of malignancy. Integrins alpha v beta 3 and alpha v beta 5 were expressed in many glioma vessels; the intensity of vascular expression of alpha v beta 3 increased with grade of malignancy, whereas alpha v beta 8 was absent. Analysis of gene expression in an independent cohort showed a similar increase in integrin expression with tumor grade, particularly of ITGB3 and ITGB8; ITGB6 was not expressed, consistent with the IHC data. Parenchymal alpha v beta 3 expression and ITGB3 gene overexpression in glioblastomas were associated with a poor prognosis, as revealed by survival analysis (Kaplan-Meier logrank, p = 0.016). Together, these data strengthen the rationale for anti-integrin treatment of glial tumors.