Friend or foe? The elusive role of hepatic stellate cells in liver cancer

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.

Automated summary

Liver fibrosis is a significant risk factor for liver cancer development and progression. Recent studies have identified specific subpopulations of hepatic stellate cells (HSCs) and cancer-associated fibroblasts (CAFs) that play dual roles in promoting or preventing fibrosis and cancer. Integrative analysis of single-cell transcriptomics and spatial RNA sequencing data has revealed the heterogeneity among these subpopulations and their distinct gene expression signatures and functions. Understanding these roles and pathways will contribute to the development of biomarkers, prognosis assessment, and new therapies for liver cancer prevention and treatment.