Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany.
J Neuropathol Exp Neurol. 2013 Mar;72(3):194-210. doi: 10.1097/NEN.0b013e3182851019.
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.
针对αv 系列整合素的整合素抑制剂正在对脑肿瘤患者进行治疗潜力的测试，但由于缺乏适合福尔马林固定、石蜡包埋标本免疫组织化学 (IHC) 的抗体，病理研究受到限制。我们使用针对αvβ3、αvβ5、αvβ6 和αvβ8 复合物的新兔单克隆抗体，通过手动和自动化显微镜分析，在公共数据库中使用基因表达数据，比较了脑肿瘤和正常人类脑组织中αv 整合素的表达，通过 IHC。神经胶质瘤通常具有αvβ3 阳性/αvβ5 阳性/αvβ8 阳性/αvβ6 阴性表型。在 94 例 WHO（世界卫生组织）二级星形细胞瘤、85 例间变性星形细胞瘤 WHO 三级和 324 例来自存档来源的胶质母细胞瘤中，整合素的表达通常随着恶性程度的增加而增加。整合素αvβ3 和αvβ5 在许多神经胶质瘤血管中表达；血管中αvβ3 的表达强度随着恶性程度的增加而增加，而αvβ8 则不存在。对独立队列中基因表达的分析表明，整合素表达随着肿瘤分级的增加而增加，特别是 ITGB3 和 ITGB8；ITGB6 不表达，与 IHC 数据一致。胶质母细胞瘤中实质αvβ3 表达和 ITGB3 基因过表达与预后不良相关，通过生存分析（Kaplan-Meier logrank，p = 0.016）证实。综上所述，这些数据为抗整合素治疗神经胶质瘤提供了更充分的依据。
