Affiliations
- 1Department of Microbiology and Immunology, National University of Singapore, Singapore.
- 2Mechanobiology Institute, National University of Singapore, Singapore.
- 3Department of Biomedical Engineering, National University of Singapore, Singapore; The N.1 Institute for Health, National University of Singapore, Singapore.
- 4Cancer Science Institute of Singapore, National University of Singapore, Singapore.
- 5Department of Biomedical Engineering, National University of Singapore, Singapore.
- 6Faculty of Medicine, Memorial University of Newfoundland, Canada.
- 7Department of Hepato-Pancreato-Biliary (HPB) and Transplant Surgery, Singapore General Hospital, Singapore; Surgery Academic-Clinical Program, Duke-NUS Medical School Singapore, Singapore; National Cancer Centre Singapore, Singapore.
- 8Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore.
- 9Department of Biomedical Engineering, National University of Singapore, Singapore; The N.1 Institute for Health, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, Singapore; NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: edwardkchow@nus.edu.sg.
- 10The N.1 Institute for Health, National University of Singapore, Singapore; Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Electronic address: lsittb@nus.edu.sg.
- 11Department of Biomedical Engineering, National University of Singapore, Singapore; The N.1 Institute for Health, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore. Electronic address: bieflse@nus.edu.sg.
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer worldwide. Despite approvals of several therapeutics to treat advanced HCC in the past few years, the impact of anti-angiogenic treatment on HCC patient overall survival remains limited. This suggests there may be alternative, perfusion-independent roles of endothelial cells that support tumor progression. Thus, we leveraged a well-defined hydrogel system to establish co-culture models to mimic and characterize the angiocrine crosstalk between HCC and endothelial cells in vitro. Co-cultures of HCC cell lines or patient-derived xenograft organoids with endothelial cells exhibited the upregulation of MCP-1, IL-8 and CXCL16, suggesting that the HCC-endothelial interactions established in our models recapitulate known angiocrine signaling. Additionally, by subjecting co-cultures and mono-cultures to RNA sequencing, transcriptomic analysis revealed an upregulation in the expression of genes associated with tumor necrosis factor (TNF) signaling, such as that of chemokines, suggesting that endothelial cells induce HCC cells to generate an inflammatory microenvironment by recruiting immune cells. Finally, HCC-endothelial angiocrine crosstalk in the co-culture models polarized macrophages towards a pro-inflammatory and pro-angiogenic phenotype, paralleling a tumor-associated macrophage subset previously reported in HCC. Together, these findings suggest that these HCC-endothelial co-culture models may serve as important models to understand and target the interplay between angiogenesis and the immune milieu.
PMID: 35483200 DOI: 10.1016/j.biomaterials.2022.121527