Bimodal anti-glioma mechanisms of cilengitide demonstrated by novel invasive glioma models.
Bimodal anti-glioma mechanisms of cilengitide demonstrated by novel invasive glioma models.
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DOI：
10.1111/j.1440-1789.2012.01344.x
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发表时间：
2013-04
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通讯作者：
Date I
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作者：
Onishi M;Ichikawa T;Kurozumi K;Fujii K;Yoshida K;Inoue S;Michiue H;Chiocca EA;Kaur B;Date I
整合素在肿瘤细胞和肿瘤内皮细胞中表达，可能在胶质瘤血管生成和侵袭中起重要作用。我们利用新型侵袭性胶质瘤模型J3 T-1和J3 T-2研究了αvβ3整合素抑制剂西仑吉肽（Cilengitide，EMD 121974）的抗胶质瘤作用机制。免疫组织化学染色显示αvβ3整合素在J3 T-2细胞和肿瘤内皮细胞中呈阳性表达，而在J3 T-1细胞中不表达。用西仑吉肽或溶剂处理在无胸腺大鼠中建立的J3 T-1和J3 T-2原位胶质瘤。J3 T-1胶质瘤表现出血管周围肿瘤簇形成和血管生成，而J3 T-2胶质瘤表现出弥漫性单细胞浸润，没有明显的血管生成。与对照组相比，西仑吉肽治疗导致J3 T-1肿瘤血管簇及其核心血管的直径显著减小，而在J3 T-2胶质瘤中显示出抗侵袭作用，肿瘤中心周围的弥漫性细胞浸润显著减少。西仑吉肽治疗的携带J3 T-1肿瘤的小鼠的生存期显著长于对照动物（中位生存期;分别为57.5天和31.8天，P < 0.005），而西仑吉肽对携带J3 T-2肿瘤的小鼠的生存期没有影响（中位生存期;分别为48.9天和48.5天，P = 0.69）。我们的研究结果表明西仑吉肽通过抑制血管生成和胶质瘤细胞侵袭发挥表型抗肿瘤作用。这两种机制通过两种不同的动物侵袭性胶质瘤模型的实验治疗清楚地显示。
Integrins are expressed in tumor cells and tumor endothelial cells, and likely play important roles in glioma angiogenesis and invasion. We investigated the anti-glioma mechanisms of cilengitide (EMD121974), an αvβ3 integrin inhibitor, utilizing the novel invasive glioma models, J3T-1and J3T-2. Immunohistochemical staining of cells in culture and brain tumors in rats revealed positive αvβ3 integrin expression in J3T-2 cells and tumor endothelial cells, but not in J3T-1 cells. Established J3T-1 and J3T-2 orthotopic gliomas in athymic rats were treated with cilengitide or solvent. J3T-1 gliomas showed perivascular tumor cluster formation and angiogenesis, while J3T-2 gliomas showed diffuse single-cell infiltration without obvious angiogenesis. Cilengitide treatment resulted in a significantly decreased diameter of the J3T-1 tumor vessel clusters and its core vessels when compared with controls, while an anti-invasive effect was shown in the J3T-2 glioma with a significant reduction of diffuse cell infiltration around the tumor center. The survival of cilengitide-treated mice harboring J3T-1 tumors was significantly longer than that of control animals (median survival; 57.5 days and 31.8 days, respectively, P < 0.005), while cilengitide had no effect on the survival of mice with J3T-2 tumors (median survival; 48.9 days and 48.5, P = 0.69). Our results indicate that cilengitide exerts a phenotypic anti-tumor effect by inhibiting angiogenesis and glioma cell invasion. These two mechanisms are clearly shown by the experimental treatment of two different animal invasive glioma models.