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Semin Liver Dis 2025; 45(01): 033-051
DOI: 10.1055/a-2551-0724
Review Article

Hepatic Stellate Cells Functional Heterogeneity in Liver Cancer

Laura Sererols-Viñas   *
1   Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
2   University of Barcelona, Barcelona, Spain
,
Gemma Garcia-Vicién   *
1   Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
,
Paloma Ruiz-Blázquez
2   University of Barcelona, Barcelona, Spain
3   Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain
4   Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain
5   CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
,
Ting-Fang Lee
6   Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
,
Youngmin A. Lee
6   Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
,
Ester Gonzalez-Sanchez
7   HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
8   Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
,
Javier Vaquero
5   CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
7   HepatoBiliary Tumours Lab, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
9   TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
,
Anna Moles
3   Tissue Remodeling Fibrosis and Cancer Group, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Spain
4   Institute of Biomedical Research of Barcelona (IDIBAPS), Barcelona, Spain
5   CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain
,
Aveline Filliol   #
10   Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
,
Silvia Affò   #
1   Tumor Microenvironment Plasticity and Heterogeneity Research Group, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
› Author Affiliations Funding S.A. is funded by the RYC2022-036321-I, MCIN/AEI/10.13039/501100011033/FEDER, Project PID2021-124694OA-I00, and The European Union grant agreement 101077312*. This work was also funded, in part, through the NIH/NCI Cancer Center Support Core Grant P30 CA008748 to A.A.F.; Y.A.L. is supported by 1R01DK133512 RSG-22-061-01-MM; A.M. is funded by MCIN/AEI/10.13039/501100011033/FEDER, UE through the project grant PID2021-123652OB-I00 and Pfizer grant #77131383; P.R.B. is funded by Ministerio de Universidades fellowships FPU19/05357. J.V. is funded by AEI, MICIN, through the project grant PID2022-141984OB-I00 and the “Ramon y Cajal” program RYC2021-034121-I.
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*Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them.
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Abstract

Hepatic stellate cells (HSCs) are the liver's pericytes, and play key roles in liver homeostasis, regeneration, fibrosis, and cancer. Upon injury, HSCs activate and are the main origin of myofibroblasts and cancer-associated fibroblasts (CAFs) in liver fibrosis and cancer. Primary liver cancer has a grim prognosis, ranking as the third leading cause of cancer-related deaths worldwide, with hepatocellular carcinoma (HCC) being the predominant type, followed by intrahepatic cholangiocarcinoma (iCCA). Moreover, the liver hosts 35% of all metastatic lesions. The distinct spatial distribution and functional roles of HSCs across these malignancies represent a significant challenge for universal therapeutic strategies, requiring a nuanced and tailored understanding of their contributions. This review examines the heterogeneous roles of HSCs in liver cancer, focusing on their spatial localization, dynamic interactions within the tumor microenvironment (TME), and emerging therapeutic opportunities, including strategies to modulate their activity, and harness their potential as targets for antifibrotic and antitumor interventions.

Keywords

hepatic stellate cells - liver cancer - cancer-associated fibroblasts - tumor microenvironment

* Co-first authors, equal contribution.


# Co-last and corresponding authors.




Publication History

Accepted Manuscript online:
05 March 2025

Article published online:
29 March 2025

© 2025. Thieme. All rights reserved.

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