VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance.
VEGF-C sustains VEGFR2 activation under bevacizumab therapy and promotes glioblastoma maintenance.
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DOI：
10.1093/neuonc/noy103
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发表时间：
2018-10-09
期刊：
影响因子：
15.9
通讯作者：
Hamerlik P
中科院分区：
文献类型：
--
作者：
Michaelsen SR;Staberg M;Pedersen H;Jensen KE;Majewski W;Broholm H;Nedergaard MK;Meulengracht C;Urup T;Villingshøj M;Lukacova S;Skjøth-Rasmussen J;Brennum J;Kjær A;Lassen U;Stockhausen MT;Poulsen HS;Hamerlik P
胶质母细胞瘤是最致命的癌症之一，目前的治疗方法只能治标不治本。旁分泌血管内皮生长因子（VEGF）信号传导已被使用抗血管生成剂靶向，而自分泌VEGF/VEGF受体2（VEGFR 2）信号传导知之甚少。表达VEGFR 2的胶质母细胞瘤细胞的贝伐单抗耐药性促使了胶质母细胞瘤中自分泌VEGF-C/VEGFR 2信号转导的研究。使用RNA干扰和外源性配体在体外和体内对患者来源的异种移植物系和原代胶质母细胞瘤细胞培养物中的自分泌VEGF-C/VEGFR 2信号传导进行了功能性研究。通过免疫组织化学和邻位连接试验分析了匹配的贝伐珠单抗治疗前后队列中VEGF-C表达及其与VEGFR 2的相互作用。VEGF-C在贝伐单抗治疗前后由患者来源的异种移植胶质母细胞瘤细胞系、原代细胞和匹配的手术标本表达。VEGF-C激活自分泌VEGFR 2信号以促进细胞存活，而靶向VEGF-C表达重编程细胞转录以减弱存活和细胞周期进展。支持潜在的翻译意义，靶向VEGF-C损害体内肿瘤生长，优于贝伐珠单抗治疗。我们的研究结果表明VEGF-C在胶质母细胞瘤中作为旁分泌和自分泌促生存细胞因子，促进肿瘤细胞存活和肿瘤发生。VEGF-C允许持续的VEGFR 2活化和肿瘤生长，其中其抑制在改善肿瘤控制方面表现出优于贝伐单抗治疗的上级。
Glioblastoma ranks among the most lethal cancers, with current therapies offering only palliation. Paracrine vascular endothelial growth factor (VEGF) signaling has been targeted using anti-angiogenic agents, whereas autocrine VEGF/VEGF receptor 2 (VEGFR2) signaling is poorly understood. Bevacizumab resistance of VEGFR2-expressing glioblastoma cells prompted interrogation of autocrine VEGF-C/VEGFR2 signaling in glioblastoma. Autocrine VEGF-C/VEGFR2 signaling was functionally investigated using RNA interference and exogenous ligands in patient-derived xenograft lines and primary glioblastoma cell cultures in vitro and in vivo. VEGF-C expression and interaction with VEGFR2 in a matched pre- and post-bevacizumab treatment cohort were analyzed by immunohistochemistry and proximity ligation assay. VEGF-C was expressed by patient-derived xenograft glioblastoma lines, primary cells, and matched surgical specimens before and after bevacizumab treatment. VEGF-C activated autocrine VEGFR2 signaling to promote cell survival, whereas targeting VEGF-C expression reprogrammed cellular transcription to attenuate survival and cell cycle progression. Supporting potential translational significance, targeting VEGF-C impaired tumor growth in vivo, with superiority to bevacizumab treatment. Our results demonstrate VEGF-C serves as both a paracrine and an autocrine pro-survival cytokine in glioblastoma, promoting tumor cell survival and tumorigenesis. VEGF-C permits sustained VEGFR2 activation and tumor growth, where its inhibition appears superior to bevacizumab therapy in improving tumor control.
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