β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma.
β1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma.
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DOI：
10.1158/0008-5472.can-13-0011
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发表时间：
2013-05-15
期刊：
影响因子：
11.2
通讯作者：
Aghi MK
中科院分区：
文献类型：
--
作者：
Carbonell WS;DeLay M;Jahangiri A;Park CC;Aghi MK
抗血管生成疗法，如贝伐单抗，为癌症治疗提供了希望，但获得性耐药性，通常包括侵袭性间充质表型，可以限制这些药物的使用。β1整联蛋白（ITGB 1）的上调发生在一些贝伐珠单抗耐药胶质母细胞瘤（BRG）中，介导肿瘤微环境相互作用，我们假设它可能介导间充质型抗血管生成治疗耐药。β1整合素及其下游效应激酶FAK的免疫染色分析显示，与治疗前配对标本相比，分别有75%和86%的BRG上调。此外，流式细胞术显示，与贝伐珠单抗初治胶质母细胞瘤（BNG）细胞相比，原代BRG细胞中的β1整合素多8倍。对表达β1-GFP融合蛋白的细胞进行光漂白后的荧光恢复表明，与贝伐珠单抗反应性多形性胶质母细胞瘤细胞相比，BRG细胞中移动的β1整联蛋白部分加倍，并且局灶性粘连中β1整联蛋白周转的半衰期显著缩短。缺氧（随着贝伐单抗耐药的获得而增加）与培养的BNG细胞中β1整合素表达增加相关。BRG在体外表现出侵袭性间充质样表型。我们发现BRG异种移植肿瘤的生长被β1抗体OS 2966减弱，使得该模型中每个周期的贝伐珠单抗剂量减少20倍。通过渗透泵颅内递送OS 2966超过28天增加了肿瘤细胞凋亡，降低了肿瘤细胞侵袭性，并钝化了肿瘤细胞的间质形态。我们得出结论，BRG中β1整合素上调可能反映了抗血管生成治疗引起的缺氧发作，并且β1抑制剂作为破坏对该治疗的耐药性的易处理策略在体内耐受性良好。
Antiangiogenic therapies like bevacizumab offer promise for cancer treatment, but acquired resistance, which often includes an aggressive mesenchymal phenotype, can limit the use of these agents. Upregulation of β1 integrin (ITGB1) occurs in some bevacizumab-resistant glioblastomas (BRG) whereby, mediating tumor–microenvironment interactions, we hypothesized that it may mediate a mesenchymal-type resistance to antiangiogenic therapy. Immunostaining analyses of β1 integrin and its downstream effector kinase FAK revealed upregulation in 75% and 86% of BRGs, respectively, compared with pretreatment paired specimens. Furthermore, flow cytometry revealed eight-fold more β1 integrin in primary BRG cells compared with cells from bevacizumab-naïve glioblastomas (BNG). Fluorescence recovery after photobleaching of cells engineered to express a β1-GFP fusion protein indicated that the mobile β1 integrin fraction was doubled, and half-life of β1 integrin turnover in focal adhesions was reduced markedly in BRG cells compared with bevacizumab-responsive glioblastoma multiforme cells. Hypoxia, which was increased with acquisition of bevacizumab resistance, was associated with increased β1 integrin expression in cultured BNG cells. BRGs displayed an aggressive mesenchymal-like phenotype in vitro. We found that growth of BRG xenograft tumors was attenuated by the β1 antibody, OS2966, allowing a 20-fold dose reduction of bevacizumab per cycle in this model. Intracranial delivery of OS2966 through osmotic pumps over 28 days increased tumor cell apoptosis, decreased tumor cell invasiveness, and blunted the mesenchymal morphology of tumor cells. We concluded that β1 integrin upregulation in BRGs likely reflects an onset of hypoxia caused by antiangiogenic therapy, and that β1 inhibition is well tolerated in vivo as a tractable strategy to disrupt resistance to this therapy.