Longitudinal expression analysis of ??v integrins in human gliomas reveals upregulation of integrin ??v??3 as a negative prognostic factor

摘要

Integrin inhibitors targeting ??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 ??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 ??v??3, ??v??5, ??v??6, and ??v??8 complexes using both manual and automated microscopy analyses. Glial tumors usually shared an ??v??3-positive/ ??v??5-positive/??v??8-positive/??v??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 ??v??3 and ??v??5 were expressed in many glioma vessels; the intensity of vascular expression of ??v??3 increased with grade of malignancy, whereas ??v??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 ??v??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. ? 2013 American Association of Neuropathologists, Inc.