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首页> 外文期刊>Neoplasia: an international journal for oncology research >Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma
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Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma

机译：细胞适应对VEGF靶向抗血管生成治疗诱导肾细胞癌中替代内皮细胞生长因子过量产生的抗抗抗性

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Vascular endothelial growth factor (VEGF)–targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC.
机译：血管内皮生长因子（VEGF） - 可抑制抗血管生成治疗显着抑制透明细胞肾细胞癌（RCC）的生长。最终，治疗抵抗甚至最敏感的病例发生，但阻力机制仍然不清楚。在此，我们通过将亲本细胞调节到由VEGF靶向治疗（Sunitinib暴露和缺氧）引起的两种不同应力来制定两种肿瘤模型，以研究RCC抗性对这种治疗的抵抗机制。与父母细胞相比，体外的Sunitinib调节Caki-1细胞没有显示出对孙尼替尼的抵抗力，但是当在体内进行测试时，这些细胞似乎对晒碱治疗具有高度抗性。缺氧调节的CAKI-1细胞对缺氧具有更大的抗缺氧，并且由于VEGF生产的上调，血管性增加;然而，它们在体外或体内没有发展阳光碱性抗性。与父母细胞相比，人类内皮细胞更增殖，并在别智尼调节CAKI-1细胞中显示出条件培养基中的管形成。基因表达分析使用RNA微阵列揭示了与组织发育和改造有关的几种基因，包括内皮细胞的发育和迁移，与亲本和缺氧调节细胞相比，在享乐initInib调节Caki-1细胞中上调。这些研究结果表明，通过通过与VEGF靶向药物的相互作用诱导的VEGF无关的血管生成途径来获得对VEGF靶向治疗的抗抗抗抗性抗性抗性靶向治疗的抗性，但不是缺氧。这些结果强调，需要增加肿瘤血管生成的抑制，以推迟抗抗原治疗的抗性并维持RCC的治疗反应。

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