Plasmalemma vesicle-associated protein promotes angiogenesis in cholangiocarcinoma via the DKK1/CKAP4/PI3K signaling pathway
Plasmalemma vesicle-associated protein promotes angiogenesis in cholangiocarcinoma via the DKK1/CKAP4/PI3K signaling pathway
复制标题
质膜囊泡相关蛋白通过 DKK1/CKAP4/PI3K 信号通路促进胆管癌血管生成
DOI：
10.1038/s41388-021-01844-z
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发表时间：
2021-06-02
期刊：
影响因子：
8
通讯作者：
Chen, Gang
中科院分区：
文献类型：
--
作者：
Wang, Yi;Yu, Haitao;Chen, Gang
胆管癌（CCA）是一种侵袭性肿瘤，由于诊断延迟和缺乏有效的非手术治疗方案，临床预后差。近年来的研究表明，质膜囊泡相关蛋白（plasmalemma vesicle-associated protein，PLVAP）与多种肿瘤的血管生成有关，体内PLVAP靶向治疗已被证实对肝细胞癌和胰腺癌有效。本研究的目的是确定靶向PLVAP的潜在治疗效用，从而在CCA中血管生成，并探索潜在的分子机制。我们发现，PLVAP的表达水平显着较高的CCA组织相比，匹配的相邻的非肿瘤组织从共90例CCA患者; PLVAP的表达水平较高，与患者的总生存期较短。此外，PLVAP过表达与CCA组织中较高的微血管密度相关。在PLVAP过表达CCA患者来源的异种移植模型中，新型人源化抗PLVAP抗体与吉西他滨加顺铂的组合显著抑制肿瘤生长。对与人脐静脉内皮细胞或人肝窦内皮细胞共培养的CCA细胞的分子分析表明，CCA细胞分泌的Dickkopf相关蛋白1（DKK 1）与其受体细胞凋亡相关蛋白4（CKAP 4）结合后激活PI 3 K/Akt通路，导致PLVAP上调。因此，CCA细胞以旁分泌方式增加了内皮细胞的血管生成能力。因此，CKAP 4和PLVAP过表达的肿瘤患者预后不良。总之，DKK 1/CKAP 4/PI 3 K/PLVAP通路增加CCA中的血管生成，因此是潜在的抗血管生成靶点。
Cholangiocarcinoma (CCA) is aggressive and has poor clinical outcomes because of typically delayed diagnosis and a lack of effective non-surgical therapeutic options. Recent studies have shown that plasmalemma vesicle-associated protein (PLVAP) is related to angiogenesis in various tumors, and in vivo PLVAP targeting therapy has been proven effective against hepatocellular carcinoma and pancreatic cancer. The goal of this study was to determine the potential therapeutic utility of targeting PLVAP and thus angiogenesis in CCA and explore the underlying molecular mechanisms. We found that the PLVAP expression levels were significantly higher in CCA tissues when compared with matched adjacent non-tumor tissues obtained from a total of 90 CCA patients; higher expression levels of PLVAP were associated with shorter overall survival of patients. In addition, overexpression of PLVAP was associated with higher micro-vessel density in CCA tissues. In a PLVAP overexpressing CCA patient-derived xenograft model, a novel humanized anti-PLVAP antibody in combination with Gemcitabine plus Cisplatin was significantly inhibited tumor growth. Molecular analysis of CCA cells co-cultured with human umbilical vascular endothelial cells or human hepatic sinusoidal endothelial cells showed that Dickkopf-related protein 1 (DKK1) secreted by CCA cells activated the PI3K/Akt pathway after binding to its receptor, cytoskeleton-associated protein 4 (CKAP4), resulting in the upregulation of PLVAP. Thus, CCA cells increased the angiogenic potency of endothelial cells in a paracrine fashion. Consistently, patients bearing CKAP4 and PLVAP overexpressing tumors had a poor prognosis. In conclusion, the DKK1/CKAP4/PI3K/PLVAP pathway increases angiogenesis in CCA and is therefore a potential anti-angiogenic target.