Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China.
Department of Infectious Diseases, Shanxi Provincial People's Hospital, Taiyuan, China.
J Cancer Res Clin Oncol. 2023 Aug;149(10):7703-7716. doi: 10.1007/s00432-023-04722-1. Epub 2023 Mar 31.
Targeting angiogenesis is an attractive strategy for the effective treatment of cancer. This study aimed to investigate the anti-cancer activities of YAP inhibitor verteporfin (VP) in esophageal squamous cell carcinoma (ESCC) cells through its inhibitory effect on tumor angiogenesis.
Cell proliferation, apoptosis, migration and invasion abilities were estimated by MTT, colony formation, DAPI staining, wound healing and transwell assays, respectively. Human umbilical vein endothelial cell (HUVEC) tube formation assay and chick embryo chorioallantoic membrane (CAM) model were used to observe angiogenesis in vitro and in vivo. The interactions between ESCC cells and HUVECs were assessed by cell chemotactic migration and adhesion assays. The expression levels of angiogenesis-related molecules were detected by Western blot.
We found that VP was potential to inhibit ESCC cell proliferation, migration, invasion and induce apoptosis in the dose-dependent fashion. VP also significantly suppressed proliferation, migration, and tube formation of HUVECs and promoted apoptosis of HUVECs, and reduced angiogenesis in CAM. Moreover, VP inhibited ESCC cell-induced angiogenesis in vitro by decreasing HUVEC chemotactic migration, adhesion and tube formation, and also reduced ESCC cell-induced neovascularization of the CAM in vivo. In addition, VP suppressed the expression of pro-angiogenic molecules such as VEGFA, MMP-2 and β-catenin in ESCC cells. Furtherly, VP increased the chemosensitivity of ESCC-resistant cells to paclitaxel (PTX). The combination of VP and PTX attenuated the resistant cell-mediated angiogenesis in vitro and in vivo.
These results reveal for the first time that VP potently inhibits malignant progression and overcomes chemoresistance of ESCC cells via inhibition of tumor angiogenesis. It provides insight into a new strategy for the treatment of ESCC that VP could be a potential drug candidate for targeting tumor angiogenesis.
靶向血管生成是治疗癌症的有效策略。本研究旨在通过抑制肿瘤血管生成来研究 YAP 抑制剂维替泊芬（VP）对食管鳞癌细胞（ESCC）的抗癌活性。
通过 MTT、集落形成、DAPI 染色、划痕愈合和 Transwell 分析分别评估细胞增殖、凋亡、迁移和侵袭能力。用人脐静脉内皮细胞（HUVEC）管形成实验和鸡胚绒毛尿囊膜（CAM）模型观察体外和体内血管生成。通过细胞趋化迁移和黏附实验评估 ESCC 细胞与 HUVEC 之间的相互作用。通过 Western blot 检测血管生成相关分子的表达水平。
我们发现 VP 能够潜在地抑制 ESCC 细胞增殖、迁移、侵袭并诱导细胞凋亡，且呈剂量依赖性。VP 还显著抑制 HUVEC 的增殖、迁移和管形成，并促进 HUVEC 的凋亡，减少 CAM 中的血管生成。此外，VP 通过减少 HUVEC 的趋化迁移、黏附和管形成来抑制 ESCC 细胞诱导的体外血管生成，还减少了体内 ESCC 细胞诱导的 CAM 新生血管化。此外，VP 抑制 ESCC 细胞中促血管生成分子如 VEGFA、MMP-2 和 β-连环蛋白的表达。此外，VP 增加了 ESCC 耐药细胞对紫杉醇（PTX）的化疗敏感性。VP 和 PTX 的联合减弱了体外和体内耐药细胞介导的血管生成。
这些结果首次揭示 VP 通过抑制肿瘤血管生成，强力抑制 ESCC 细胞的恶性进展并克服其化疗耐药性。这为治疗 ESCC 提供了新策略，表明 VP 可能是一种用于靶向肿瘤血管生成的潜在药物候选物。
