Liver fibrosis is a substantial risk factor for the development and progression of liver cancer, which includes hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Studies utilizing cell fate mapping and single-cell transcriptomics techniques have identified quiescent perisinusoidal hepatic stellate cells (HSCs) as the primary source of activated collagen-producing HSCs and liver cancer-associated fibroblasts (CAFs) in HCC and liver metastasis, complemented in iCCA by contributions from portal fibroblasts. At the same time, integrative computational analysis of single-cell, single-nucleus and spatial RNA sequencing data have revealed marked heterogeneity among HSCs and CAFs, with distinct subpopulations displaying unique gene expression signatures and functions. Some of these subpopulations have divergent roles in promoting or inhibiting liver fibrogenesis and carcinogenesis. In this Review, we discuss the dual roles of HSC subpopulations in liver fibrogenesis and their contribution to liver cancer promotion, progression and metastasis. We review the transcriptomic and functional similarities between HSC and CAF subpopulations, highlighting the pathways that either promote or prevent fibrosis and cancer, and the immunological landscape from which these pathways emerge. Insights from ongoing studies will yield novel strategies for developing biomarkers, assessing prognosis and generating new therapies for both HCC and iCCA prevention and treatment.
Hepatic stellate cells (HSCs) are the major source of activated myofibroblast-like cells in liver fibrosis and cancer-associated fibroblasts (CAFs) in both primary and metastatic liver cancer.
Single-cell resolution technologies are unveiling the transcriptomic and phenotypic heterogeneity of HSCs and CAFs in mouse models of liver disease and in humans.
Specific subpopulations of HSCs and CAFs exhibit contrasting tumour-promoting and tumour-inhibitory functions based on their immunological and tumour-specific context.
HSC subpopulations with unique secretomes, including activated HSCs, senescent HSCs and CAFs, are promising targets for antifibrotic therapies that might reduce the risk of liver cancer, especially in patients with nonalcoholic steatohepatitis.
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Grant Support: São Paulo Research Foundation (FAPESP, 2022/02175-1); Medical Scientist Training Program Training Grant (T32GM007280); NCI-funded Training Program in Cancer Biology (NCI T32CA078207-22); American Gastroenterological Association Research Scholar (AGA2020-13-03); 1R01 DK136016-01; Tisch Cancer Institute (Icahn School of Medicine at Mount Sinai), F. Klion Award; i3 Genesis Award; TCI Dev. Funds Award 2023; 5R01DK128289-03; 5R01 DK121154-04; and 5P30CA196521-08.
The authors declare no competing interests.
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Cogliati, B., Yashaswini, C.N., Wang, S. et al. Friend or foe? The elusive role of hepatic stellate cells in liver cancer. Nat Rev Gastroenterol Hepatol 20, 647–661 (2023). https://doi.org/10.1038/s41575-023-00821-z