Wang Yi, Yu Haitao, Xie Xiaozai, Deng Tuo, Ye Longyun, Wu Lijun, Ding Xiwei, Yang Zhen, Zhu Qiandong, Li Junjian, Zheng Yihu, Yu Zhengping, Chen Gang
Division of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Oncogene. 2021 Jun;40(25):4324-4337. doi: 10.1038/s41388-021-01844-z. Epub 2021 Jun 2.
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.
胆管癌（CCA）侵袭性强，临床预后差，原因通常是诊断延迟且缺乏有效的非手术治疗选择。最近的研究表明，质膜囊泡相关蛋白（PLVAP）与多种肿瘤的血管生成有关，体内靶向PLVAP治疗已被证明对肝细胞癌和胰腺癌有效。本研究的目的是确定靶向PLVAP从而抑制CCA血管生成的潜在治疗效用，并探索其潜在的分子机制。我们发现，与从总共90例CCA患者获得的配对相邻非肿瘤组织相比，CCA组织中PLVAP的表达水平显著更高；PLVAP表达水平较高与患者较短的总生存期相关。此外，PLVAP的过表达与CCA组织中较高的微血管密度相关。在一个过表达PLVAP的CCA患者来源的异种移植模型中，一种新型人源化抗PLVAP抗体联合吉西他滨加顺铂可显著抑制肿瘤生长。对与人类脐血管内皮细胞或人类肝窦内皮细胞共培养的CCA细胞进行分子分析表明，CCA细胞分泌的Dickkopf相关蛋白1（DKK1）与其受体细胞骨架相关蛋白4（CKAP4）结合后激活PI3K/Akt途径，导致PLVAP上调。因此，CCA细胞以旁分泌方式增加内皮细胞的血管生成能力。同样，携带CKAP4和PLVAP过表达肿瘤的患者预后较差。总之，DKK1/CKAP4/PI3K/PLVAP途径增加了CCA的血管生成，因此是一个潜在的抗血管生成靶点。
