A biomimetic liver cancer on-a-chip reveals a critical role of LIPOCALIN-2 in promoting hepatocellular carcinoma progression  

作　　者：Peiliang Shen Yuanyuan Jia Weijia Zhou Weiwei Zheng Yueyao Wu Suchen Qu Shiyu Du Siliang Wang Huilian Shi Jia Sun Xin Han 

机构地区：[1]Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica,School of Medicine&Holistic Integrative Medicine,Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China [2]Department of Pharmacy,Nanjing Drum Tower Hospital,The Affiliated Hospital of Nanjing University Medical School,Nanjing 210008,China [3]Nanjing Medical Center for Clinical Pharmacy,Nanjing 210008,China [4]Department of Infectious Diseases,Jiangsu Province Hospital of Chinese Medicine,Affiliated Hospital of Nanjing University of Chinese Medicine,Nanjing 210023,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第11期4621-4637,共17页药学学报（英文版）

基　　金：funded by National Natural Science Foundation of China (Nos.31901010 and 81803916,China);Natural Science Foundation of Jiangsu Province (grant No.BK20180128,China);The Priority Academic Program Development of Jiangsu Higher Education Institutions (Integration of Chinese and Western Medicine,China);Jiangsu Specially Appointed Professorship;Jiangsu Key Discipline Construction Fund of the 14th Five-Year Plan (Biology,China);The Graduate Research&Practice Innovation Program of Jiangsu Province (KYCX21_1743,KYCX22_1992,China)。

摘　　要：Hepatic stellate cells(HSCs)represent a significant component of hepatocellular carcinoma(HCC)microenvironments which play a critical role in tumor progression and drug resistance.Tumor-ona-chip technology has provided a powerful in vitro platform to investigate the crosstalk between activated HSCs and HCC cells by mimicking physiological architecture with precise spatiotemporal control.Here we developed a tri-cell culture microfluidic chip to evaluate the impact of HSCs on HCC progression.Onchip analysis revealed activated HSCs contributed to endothelial invasion,HCC drug resistance and natural killer(NK)cell exhaustion.Cytokine array and RNA sequencing analysis were combined to indicate the iron-binding protein LIPOCALIN-2(LCN-2)as a key factor in remodeling tumor microenvironments in the HCC-on-a-chip.LCN-2 targeted therapy demonstrated robust anti-tumor effects both in vitro 3D biomimetic chip and in vivo mouse model,including angiogenesis inhibition,sorafenib sensitivity promotion and NK-cell cytotoxicity enhancement.Taken together,the microfluidic platform exhibited obvious advantages in mimicking functional characteristics of tumor microenvironments and developing targeted therapies.

关 键 词：HCC-on-a-chip model Hepatic stellate cells Tumor microenvironment Endothelial invasion Sorafenib resistance NK cell Exhaustion LIPOCALIN-2 Personalized anti-cancer therapies 

分 类 号：R73[医药卫生—肿瘤]