Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors  

作　　者：Hiroyuki Suzuki Hideki Iwamoto Takahiro Seki Toru Nakamura Atsutaka Masuda Takahiko Sakaue Toshimitsu Tanaka Yasuko Imamura Takashi Niizeki Masahito Nakano Shigeo Shimose Tomotake Shirono Yu Noda Naoki Kamachi Miwa Sakai Kazutoyo Morita Masamichi Nakayama Tomoharu Yoshizumi Ryoko Kuromatsu Hirohisa Yano Yihai Cao Hironori Koga Takuji Torimura 

机构地区：[1]Division of Gastroenterology,Department of Medicine,Kurume University School of Medicine,Kurume City,Fukuoka,Japan [2]Liver Cancer Research Division,Research Center for Innovative Cancer Therapy,Kurume University,Kurume City,Fukuoka,Japan [3]Iwamoto Internal Medicine Clinic,Kitakyushu City,Fukuoka,Japan [4]Department of Microbiology,Tumor and Cell biology,Karolinska Institutet,Stockholm,Sweden [5]Department of Surgery and Science,Graduate School of Medical Science,Kyushu University,Fukuoka City,Fukuoka,Japan [6]Department of Pathology,Kurume University School of Medicine,Kurume City,Fukuoka,Japan

出　　处：《Cancer Communications》2023年第4期415-434,共20页癌症通讯（英文）

基　　金：Ishibashi Foundation for the Promotion of Science;Takeda Science Foundation;Shinnihon Foundation of Advanced Medical Treatment Research;the Kurume University Branding Project;the Yasuda Medical Foundation;the JSPS KAKENHI grant。

摘　　要：Background:Antiangiogenic tyrosine kinase inhibitors(TKIs)provide one of the few therapeutic options for effective treatment of hepatocellular carcinoma(HCC).However,patients with HCC often develop resistance toward antiangiogenic TKIs,and the underlying mechanisms are not understood.The aim of this study was to determine the mechanisms underlying antiangiogenic TKI resistance in HCC.Methods:We used an unbiased proteomic approach to define proteins that were responsible for the resistance to antiangiogenic TKIs in HCC patients.We evaluated the prognosis,therapeutic response,and serum insulin-like growth factor-binding protein-1(IGFBP-1)levels of 31 lenvatinib-treated HCC patients.Based on the array of results,a retrospective clinical study and preclinical experiments using mouse and human hepatoma cells were conducted.Additionally,in vivo genetic and pharmacological gain-and loss-of-function experiments were performed.Results:In the patient cohort,IGFBP-1 was identified as the signaling molecule with the highest expression that was inversely associated with overall survival.Mechanistically,antiangiogenic TKI treatment markedly elevated tumor IGFBP-1 levels via the hypoxia-hypoxia inducible factor signaling.IGFBP-1 stimulated angiogenesis through activation of the integrinα5β1-focal adhesion kinase pathway.Consequently,loss of IGFBP-1 and integrinα5β1 by genetic and pharmacological approaches re-sensitized HCC to lenvatinib treatment.Conclusions:Together,our data shed light onmechanisms underlying acquired resistance of HCC to antiangiogenic TKIs.Antiangiogenic TKIs induced an increase of tumor IGFBP-1,which promoted angiogenesis through activating the IGFBP-1-integrinα5β1 pathway.These data bolster the application of a new therapeutic concept by combining antiangiogenic TKIs with IGFBP-1 inhibitors.

关 键 词：hepatocellular carcinoma HYPOXIA IGFBP-1 lenvatinib molecular targeting RESISTANCE tyrosine kinase inhibitors 

分 类 号：R735.7[医药卫生—肿瘤]