Turtoi Andrei, Blomme Arnaud, Bianchi Elettra, Maris Pamela, Vannozzi Riccardo, Naccarato Antonio Giuseppe, Delvenne Philippe, De Pauw Edwin, Bevilacqua Generoso, Castronovo Vincent
Metastasis Research Laboratory, GIGA-Cancer and ‡Department of Pathology, University of Liege , Bat. B23, Liege 4000, Belgium.
J Proteome Res. 2014 Dec 5;13(12):5660-9. doi: 10.1021/pr500657w. Epub 2014 Nov 3.
Functional targeted therapy has unfortunately failed to improve the outcome of glioblastoma patients. Success stories evidenced by the use of antibody-drug conjugates in other tumor types are encouraging, but targets specific to glioblastoma and accessible through the bloodstream remain scarce. In the current work, we have identified and characterized novel and accessible proteins using an innovative proteomic approach on six human glioblastomas; the corresponding data have been deposited in the PRIDE database identifier PXD001398. Among several clusters of uniquely expressed proteins, we highlight collagen-VI-alpha-1 (COL6A1) as a highly expressed tumor biomarker with low levels in most normal tissues. Immunohistochemical analysis of glioma samples from 61 patients demonstrated that COL6A1 is a significant and consistent feature of high-grade glioma. Deposits of COL6A1 were evidenced in the perivascular regions of the tumor-associated vasculature and in glioma cells found in pseudopalisade structures. Retrospective analysis of public gene-expression data sets from over 300 glioma patients demonstrated a significant correlation of poor patient outcome and high COL6A1 expression. In a proof-of-concept study, we use chicken chorioallantoic membrane in vivo model to show that COL6A1 is a reachable target for IV-injected antibodies. The present data warrant further development of human COL6A1 antibodies for assessing the quantitative biodistribution in the preclinical tumor models.
遗憾的是，功能靶向治疗未能改善胶质母细胞瘤患者的预后。在其他肿瘤类型中使用抗体药物偶联物所证明的成功案例令人鼓舞，但胶质母细胞瘤特有的且可通过血流到达的靶点仍然稀少。在当前的工作中，我们使用创新的蛋白质组学方法对六个人类胶质母细胞瘤进行了研究，鉴定并表征了新的且可到达的蛋白质；相应的数据已存入PRIDE数据库标识符PXD001398。在几组独特表达的蛋白质中，我们重点关注了胶原蛋白-VI-α-1（COL6A1），它是一种在大多数正常组织中低水平表达但在肿瘤中高表达的肿瘤生物标志物。对61例患者的胶质瘤样本进行免疫组织化学分析表明，COL6A1是高级别胶质瘤的一个显著且一致的特征。在肿瘤相关脉管系统的血管周围区域以及假栅栏结构中的胶质瘤细胞中都发现了COL6A1的沉积。对来自300多名胶质瘤患者的公共基因表达数据集进行回顾性分析表明，患者预后不良与COL6A1高表达之间存在显著相关性。在一项概念验证研究中，我们使用鸡胚绒毛尿囊膜体内模型表明，COL6A1是静脉注射抗体可到达的靶点。目前的数据为进一步开发用于评估临床前肿瘤模型中定量生物分布的人COL6A1抗体提供了依据。
