Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma.
Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma.
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DOI：
10.1158/0008-5472.can-11-3831
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发表时间：
2012-04-01
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：
Hu YL;DeLay M;Jahangiri A;Molinaro AM;Rose SD;Carbonell WS;Aghi MK
抗血管生成治疗导致血管断流，从而限制肿瘤生长。然而，血管生成抑制剂的益处通常是短暂的，并且经常产生耐药性。在本研究中，我们探讨了抗血管生成治疗引起的缺氧诱导肿瘤细胞自噬作为细胞保护性适应性反应，从而促进治疗抵抗的假设。缺氧诱导的自噬依赖于HIF-1α/AMPK通路的信号传导，在体外用自噬抑制剂处理缺氧细胞可导致自噬细胞向凋亡细胞死亡转变。在临床对VEGF中和抗体贝伐单抗耐药的胶质母细胞瘤中，与来自同一患者的治疗前标本相比，发现缺氧区域增加和自噬介导的BNIP3水平升高。当单独使用贝伐单抗治疗时，人类胶质母细胞瘤异种移植物显示BNIP3表达增加和缺氧相关生长，这可以通过添加自噬抑制剂氯喹来预防。当与贝伐单抗联合治疗时，体内靶向必需自噬基因ATG7也会破坏肿瘤生长。总之，我们的研究结果阐明了抗血管生成治疗的一种新的抵抗机制，其中缺氧介导的自噬促进了肿瘤细胞的存活。我们发现的一个强有力的暗示是，自噬抑制剂可能有助于预防临床使用的抗血管生成治疗的耐药性。
Anti-angiogenic therapy leads to devascularization that limits tumor growth. However, the benefits of angiogenesis inhibitors are typically transient and resistance often develops. In this study, we explored the hypothesis that hypoxia caused by anti-angiogenic therapy induces tumor cell autophagy as a cytoprotective adaptive response, thereby promoting treatment resistance. Hypoxia-induced autophagy was dependent on signaling through the HIF-1α/AMPK pathway, and treatment of hypoxic cells with autophagy inhibitors caused a shift from autophagic to apoptotic cell death in vitro. In glioblastomas clinically resistant to the VEGF neutralizing antibody bevacizumab, increased regions of hypoxia and higher levels of autophagy-mediating BNIP3 were found when compared to pre-treatment specimens from the same patients. When treated with bevacizumab alone, human glioblastoma xenografts showed increased BNIP3 expression and hypoxia-associated growth, which could be prevented by addition of the autophagy inhibitor chloroquine. In vivo targeting of the essential autophagy gene ATG7 also disrupted tumor growth when combined with bevacizumab treatment. Together, our findings elucidate a novel mechanism of resistance to anti-angiogenic therapy in which hypoxia-mediated autophagy promotes tumor cell survival. One strong implication of our findings is that autophagy inhibitors may help prevent resistance to anti-angiogenic therapy used in the clinic.