A biomimetic liver cancer on-a-chip reveals a critical role of LIPOCALIN-2 in promoting hepatocellular carcinoma progression.
10.1016/j.apsb.2023.04.010
- Author:
Peiliang SHEN
1
;
Yuanyuan JIA
1
;
Weijia ZHOU
1
;
Weiwei ZHENG
1
;
Yueyao WU
1
;
Suchen QU
1
;
Shiyu DU
1
;
Siliang WANG
2
;
Huilian SHI
3
;
Jia SUN
1
;
Xin HAN
1
Author Information
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. Department of Infectious Diseases, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210023, China.
- Publication Type:Journal Article
- Keywords:
Endothelial invasion;
HCC-on-a-chip model;
Hepatic stellate cells;
LIPOCALIN-2;
NK cell Exhaustion;
Personalized anti-cancer therapies;
Sorafenib resistance;
Tumor microenvironment
- From:
Acta Pharmaceutica Sinica B
2023;13(11):4621-4637
- CountryChina
- Language:English
-
Abstract:
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-on-a-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. On-chip 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.
