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

Abstract

Integrin inhibitors targeting αv 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 αv 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 αvβ3, αvβ5, αvβ6, and αvβ8 complexes using both manual and automated microscopy analyses. Glial tumors usually shared an αvβ3-positive/αvβ5-positive/αvβ8-positive/αvβ6-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 αvβ3 and αvβ5 were expressed in many glioma vessels; the intensity of vascular expression of αvβ3 increased with grade of malignancy, whereas αvβ8 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 αvβ3 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.

Efficacy of systemic temozolomide‐activated phage‐targeted gene therapy in human glioblastoma

“…Targeting a v b 3 integrin in human GBM with RGD4C was performed in patients (Reardon et al, 2008). Previous studies reported that a v b 3 integrin can be expressed in up to 55% of human glioblastoma, depending on the tumor grade (Schnell et al, 2008;Schittenhelm et al, 2013). The a v b 3 expression was significantly higher in human GBMs than in low-grade gliomas and was seen on both activated endothelial cells and glial tumor cells existing within glioblastomas (Schnell et al, 2008;Schittenhelm et al, 2013).…”

“…Previous studies reported that a v b 3 integrin can be expressed in up to 55% of human glioblastoma, depending on the tumor grade (Schnell et al, 2008;Schittenhelm et al, 2013). The a v b 3 expression was significantly higher in human GBMs than in low-grade gliomas and was seen on both activated endothelial cells and glial tumor cells existing within glioblastomas (Schnell et al, 2008;Schittenhelm et al, 2013). In contrast, a v b 3 expression is barely detectable on normal human endothelial cells (Koch, 2000;Pap et al, 2000;Van De Wiele et al, 2002;Kumar, 2003;Gamble et al, 2010) and is also not expressed on glia or neurons in normal adult cortex and cerebral white matter (Gladson & Cheresh, 1991).…”

Integrin αVβ3 silencing sensitizes malignant glioma cells to temozolomide by suppression of homologous recombination repair

“…Moreover, the expression of αVβ3 in tumor cells and vessels, but not of other αV integrins, was shown to be dependent on tumor grade, and αVβ3 expression in tumor cells may have a prognostic impact [38]. We could show that silencing of all of the respective integrin subunits (αV, α3, α4, β3 and β5) sensitized glioblastoma cell lines to TMZ but the silencing of αVβ3 was the most powerful.…”

Alterations of gene expression and protein synthesis in co-cultured adipose tissue-derived stem cells and squamous cell-carcinoma cells: consequences for clinical applications

“…Co-culture strongly up-regulated the ITGA2B (integrin alpha 2 beta)-expression in ADSCs and ITGB3 (integrin beta 3) gene expression in A431-SCCs. Increased ITGB3 expression has been linked to an increase in migration and invasion, as well as a more aggressive phenotype of tumor cells, a progressed tumor grade and a poor prognosis [50,51]. …”