Targeting intercellular adhesion molecule-1 prolongs survival in mice bearing bevacizumab-resistant glioblastoma.
Targeting intercellular adhesion molecule-1 prolongs survival in mice bearing bevacizumab-resistant glioblastoma.
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DOI：
10.18632/oncotarget.18859
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发表时间：
2017-11-14
期刊：
影响因子：
--
通讯作者：
de Groot JF
中科院分区：
文献类型：
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作者：
Piao Y;Henry V;Tiao N;Park SY;Martinez-Ledesma J;Dong JW;Balasubramaniyan V;de Groot JF
细胞间粘附分子1（ICAM-1;也称为CD 54）在贝伐珠单抗耐药胶质母细胞瘤中过表达。在本研究中，我们验证了我们的假设，即高表达的ICAM-1介导胶质母细胞瘤对抗血管生成治疗的抵抗。我们使用实时聚合酶链反应、免疫组织化学和蛋白质印迹法验证了抗血管生成治疗耐药肿瘤中ICAM-1的过度表达。我们还检测到ICAM 1在大多数胶质瘤干细胞（GSC）中的表达。我们研究了贝伐单抗处理后ICAM-1过表达的机制，发现ICAM-1蛋白表达在体外缺氧条件下以时间依赖性的方式在GSC 11和GSC 17细胞中显著增加。我们还发现缺氧通过上调磷酸化信号转导子和转录激活子（p-STAT 3）诱导ICAM-1的过度表达。缺氧诱导的p-STAT 3增加ICAM-1的mRNA转录，我们可以用STAT 3抑制剂AZD 1480抑制。接下来，我们使用GFP标记的ICAM-1 shRNA慢病毒来敲低GSC 11和GSC 17胶质瘤细胞系中的ICAM-1。然后，我们将shICAM-1 GSC 11和scramble胶质瘤干细胞注射到裸鼠脑中。携带shICAM-1 GSC 11细胞肿瘤的小鼠比注射对照细胞的小鼠存活时间明显更长。与GFP标记的GSC 11对照细胞相比，携带shICAM-1细胞肿瘤的小鼠的肿瘤尺寸显著减小。在贝伐珠单抗处理的小鼠中，敲低ICAM-1在体外和体内抑制肿瘤侵袭，并抑制巨噬细胞浸润至肿瘤部位。我们的研究结果表明，ICAM-1是贝伐珠单抗耐药胶质母细胞瘤中肿瘤迁移和侵袭的潜在重要介质。以ICAM-1为靶点可能为增强胶质母细胞瘤抗血管生成治疗的疗效和预防疾病的侵袭性表型提供新的策略。
Intercellular cell adhesion molecule 1 (ICAM-1; also known as CD54) is overexpressed in bevacizumab-resistant glioblastoma. In the present study, we tested our hypothesis that highly expressed ICAM-1 mediates glioblastoma’s resistance to antiangiogenic therapy. We validated ICAM-1 overexpression in tumors resistant to antiangiogenic therapy using real-time polymerase chain reaction, immunohistochemistry, and Western blotting. We also detected ICAM1 expression in most glioma stem cells (GSCs). We investigated the mechanism of ICAM-1 overexpression after bevacizumab treatment and found that ICAM-1 protein expression was markedly increased in a time-dependent manner in GSC11 and GSC17 cells under hypoxic conditions in vitro. We also found that hypoxia induced ICAM-1 overexpression through the up-regulation of phosphorylated signal transducer and activator of transcription (p-STAT3). Hypoxia-induced p-STAT3 increased the mRNA transcription of ICAM-1, which we could inhibit with the STAT3 inhibitor AZD1480. Next, we used GFP-tagged ICAM-1 shRNA lentivirus to knock down ICAM-1 in GSC11 and GSC17 glioma cell lines. Then, we injected shICAM-1 GSC11 and scramble glioma stem cells into the brains of nude mice. Mice bearing tumors from shICAM-1 GSC11 cells survived significantly longer than mice injected with control cells did. The tumor sizes was significantly decreased in mice bearing tumors from shICAM-1 cells than that in mice bearing tumors from GFP-tagged GSC11 control cells. Knocking down ICAM-1 suppressed tumor invasion in vitro and in vivo and inhibited macrophage infiltration to the tumor site in bevacizumab-treated mice. Our findings suggest that ICAM-1 is a potentially important mediator of tumor migration and invasion in bevacizumab-resistant glioblastoma. Targeting ICAM-1 may provide a new strategy for enhancing the efficacy of antiangiogenic therapy against glioblastoma and preventing the invasive phenotype of the disease.