Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama 223‑8522, Japan.
Oncol Rep. 2022 Feb;47(2). doi: 10.3892/or.2021.8242. Epub 2021 Dec 16.
Vasculogenic mimicry (VM) is the formation of a blood supply system that confers aggressive and metastatic properties to tumors and correlates with a poor prognosis in cancer patients. Thus, the inhibition of VM is considered an effective approach for cancer treatment, although such a mechanism remains poorly described. In the present study, we examined methionine aminopeptidase‑2 (MetAP2), a key factor of angiogenesis, and demonstrated that it is pivotal for VM, using pharmacological and genetic approaches. Fumagillin and TNP‑470, angiogenesis inhibitors that target MetAP2, significantly suppressed VM in various human cancer cell lines. We established MetAP2‑knockout (KO) human fibrosarcoma HT1080 cells using the CRISPR/Cas9 system and found that VM was attenuated in these cells. Furthermore, re‑expression of wild‑type MetAP2 restored VM in the MetAP2‑KO HT1080 cells, but the substitution of D251, a conserved amino acid in MetAP2, failed to rescue the VM. Collectively, our results demonstrate that MetAP2 is critical for VM in human cancer cells and suggest fumagillin and TNP‑470 as potent VM‑suppressing agents.
血管生成拟态（VM）是一种形成血液供应系统的方式，赋予肿瘤侵袭性和转移性，并与癌症患者的不良预后相关。因此，抑制 VM 被认为是癌症治疗的一种有效方法，尽管这种机制仍描述不足。在本研究中，我们使用药理学和遗传学方法研究了血管生成的关键因素——甲硫氨酸氨肽酶 2（MetAP2），并证实其对 VM 至关重要。血管生成抑制剂法呢基转移酶抑制剂（FTI）和 TNP-470 靶向 MetAP2，可显著抑制多种人类癌细胞系中的 VM。我们使用 CRISPR/Cas9 系统建立了 MetAP2 敲除（KO）人纤维肉瘤 HT1080 细胞，并发现这些细胞中的 VM 受到抑制。此外，野生型 MetAP2 的重新表达可恢复 MetAP2-KO HT1080 细胞中的 VM，但 MetAP2 中保守氨基酸 D251 的取代不能挽救 VM。综上所述，我们的结果表明 MetAP2 对人类癌细胞中的 VM 至关重要，并表明法呢基转移酶抑制剂和 TNP-470 是有效的 VM 抑制因子。
