Therapeutic modulators of hepatic stellate cells for hepatocellular carcinoma

Int J Cancer. 2020 Sep 15;147(6):1519-1527. doi: 10.1002/ijc.32899. Epub 2020 Mar 5.

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary tumor in the liver and is a leading cause of cancer-related death worldwide. Activated hepatic stellate cells (HSCs) are key components of the HCC microenvironment and play an important role in the onset and progression of HCC through the secretion of growth factors and cytokines. Current treatment modalities that include chemotherapy, radiotherapy and ablation are able to activate HSCs and remodel the tumor microenvironment. Growing evidence has demonstrated that the complex interaction between activated HSCs and tumor cells can facilitate cancer chemoresistance and metastasis. Therefore, therapeutic targeting of activated HSCs has emerged as a promising strategy to improve treatment outcomes for HCC. This review summarizes the molecular mechanisms of HSC activation triggered by treatment modalities, the function of activated HSCs in HCC, as well as the crosstalk between tumor cells and activated HSCs. Pathways of activated HSC reduction are discussed, including inhibition, apoptosis, and reversion to the inactivated state. Finally, we outline the progress and challenges of therapeutic approaches targeting activated HSCs in the development of HCC treatment.

Keywords: hepatic stellate cells; hepatocellular carcinoma; therapeutic modulators.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / therapy*
  • Cell Communication / drug effects
  • Cell Communication / immunology
  • Cell Communication / radiation effects
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Chemoradiotherapy / adverse effects
  • Chemoradiotherapy / methods
  • Disease Progression
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / immunology
  • Drug Resistance, Neoplasm / radiation effects
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / immunology
  • Hepatic Stellate Cells / pathology
  • Hepatic Stellate Cells / radiation effects
  • Humans
  • Liver / blood supply
  • Liver / cytology
  • Liver / drug effects
  • Liver / pathology
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / immunology
  • Liver Neoplasms / pathology
  • Liver Neoplasms / therapy*
  • Molecular Targeted Therapy / methods
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / etiology
  • Neovascularization, Pathologic / pathology
  • Radiofrequency Ablation / adverse effects
  • Radiofrequency Ablation / methods
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Tumor Escape / drug effects
  • Tumor Escape / immunology
  • Tumor Escape / radiation effects
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Tumor Microenvironment / radiation effects