脂肪细胞中的 MCP-1/CCR-2 轴和癌细胞中的 MCP-1/CCR-2 轴分别促进卵巢癌细胞腹膜转移。
MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis.
机构信息
Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, PR China.
Cancer Genetics Laboratory of Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
出版信息
Oncogene. 2020 Feb;39(8):1681-1695. doi: 10.1038/s41388-019-1090-1. Epub 2019 Nov 8.
Abstract
Ovarian cancer selective metastasizes to the omentum contributing to the poor prognosis associated with ovarian cancer. However, the mechanism underlining this propensity and therapeutic approaches to counter this process has not been fully elucidated. Here, we show that MCP-1 produced by omental adipocytes binding to its cognate receptor CCR-2 on ovarian cancer cells facilitates migration and omental metastasis by activating the PI3K/AKT/mTOR pathway and its downstream effectors HIF-1α and VEGF-A in cell lines, xenografts, and transgenic murine models. MCP-1 antibody significantly decreased tumor burden and increased survival of mice in vivo. Interestingly, metformin decreased omental metastasis at least partially by inhibiting MCP-1 secretion from adipocytes independent of direct effects on cancer cells. Together this suggests a novel target of MCP-1/CCR-2 axis that could benefit ovarian cancer patients.
摘要
卵巢癌选择性转移至大网膜，导致与卵巢癌相关的预后不良。然而，这种倾向的发生机制以及对抗这种过程的治疗方法尚未完全阐明。在这里，我们表明，大网膜脂肪细胞产生的单核细胞趋化蛋白-1（MCP-1）与卵巢癌细胞上的同源受体 CCR-2 结合，通过激活 PI3K/AKT/mTOR 通路及其下游效应物 HIF-1α 和 VEGF-A，促进细胞系、异种移植瘤和转基因小鼠模型中的迁移和大网膜转移。MCP-1 抗体显著减少了荷瘤小鼠的肿瘤负担并提高了其存活率。有趣的是，二甲双胍至少部分地通过抑制脂肪细胞中 MCP-1 的分泌来减少大网膜转移，而这种作用不依赖于对癌细胞的直接作用。综上所述，这表明 MCP-1/CCR-2 轴是一个新的靶点，可能使卵巢癌患者受益。
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