Microbial metabolite deoxycholic acid promotes vasculogenic mimicry formation in intestinal carcinogenesis

作者：Xueli Song, Yaping An, Danfeng Chen, Wanru Zhang, Xuemei Wu, Chuqiao Li, Sinan Wang, Wenxiao Dong, Bangmao Wang, Tianyu Liu, Weilong Zhong, Tao Sun, Hailong Cao · 发表于：Cancer Science · 年份：2021 · DOI：10.1111/cas.15208 · 被引用次数：68 · 研究领域：Angiogenesis and VEGF in Cancer、Inflammatory Biomarkers in Disease Prognosis、Cancer, Stress, Anesthesia, and Immune Response

Abstract A high‐fat diet (HFD) leads to long‐term exposure to gut microbial metabolite secondary bile acids, such as deoxycholic acid (DCA), in the intestine, which is closely linked to colorectal cancer (CRC). Evidence reveals that vasculogenic mimicry (VM) is a critical event for the malignant transformation of cancer. Therefore, this study investigated the crucial roles of DCA in the regulation of VM and the progression of intestinal carcinogenesis. The effects of an HFD on VM formation and epithelial‐mesenchymal transition (EMT) in human CRC tissues were investigated. The fecal DCA level was detected in HFD‐treated Apc min/+ mice. Then the effects of DCA on VM formation, EMT, and vascular endothelial growth factor receptor 2 (VEGFR2) signaling were evaluated in vitro and in vivo. Here we demonstrated that compared with a normal diet, an HFD exacerbated VM formation and EMT in CRC patients. An HFD could alter the composition of the gut microbiota and significantly increase the fecal DCA level in Apc min/+ mice. More importantly, DCA promoted tumor cell proliferation, induced EMT, increased VM formation, and activated VEGFR2, which led to intestinal carcinogenesis. In addition, DCA enhanced the proliferation and migration of HCT‐116 cells, and induced EMT process and vitro tube formation. Furthermore, the silence of VEGFR2 reduced DCA‐induced EMT, VM formation, and migration. Collectively, our results indicated that microbial metabolite DCA promoted VM formation and EMT thr...