Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity

作     者：Guang-Yue Li Shu-Jing Zhang Dong Xue Yue-Qi Feng Yan Li Xun Huang Qiang Cui Bo Wang Jun Feng Tao Bao Pei-Jun Liu Shao-Ying Lu Ji-Chang Wang Guang-Yue Li;Shu-Jing Zhang;Dong Xue;Yue-Qi Feng;Yan Li;Xun Huang;Qiang Cui;Bo Wang;Jun Feng;Tao Bao;Pei-Jun Liu;Shao-Ying Lu;Ji-Chang Wang

作者机构：Department of Science and TechnologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Department of Vascular SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Department of General SurgeryThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Center for Translational MedicineThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Department of PharmacyXi'an Jiaotong University Health Science CenterXi'an710061China 

出 版 物：《Journal of Pharmaceutical Analysis》 (药物分析学报（英文版）)

年 卷 期：2023年第13卷第3期

页      面：262-275页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by grants from the National Natural Science Foundation of China(Grant No.:81972811) the Key Research and Development Foundation of Shaanxi Province(Grant Nos.:2018SF-099,S2021SF-136,2021JM-273,and 2022JQ-848) the Fundamental Research Funds for the Central Universities(Grant No.:xzy012022094) the Provincial Science and Technology Rising Star(Grant No.:2021KJXX-03). 

主　　题：Metformin Colorectal cancer Non-angiogenic Endothelial apoptosis Vascular immaturity 

摘      要：The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endothelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.