Emerging Role of Cancer-Associated Fibroblasts in Progression and Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death globally. Tumor cells recruit and remodel various types of stromal and inflammatory cells to form a tumor microenvironment (TME), which encompasses cellular and molecular entities, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), immune cells, myeloid-derived suppressor cells (MDSCs), immune checkpoint molecules and cytokines that promote cancer cell growth, as well as their drug resistance. HCC usually arises in the context of cirrhosis, which is always associated with an enrichment of activated fibroblasts that are owed to chronic inflammation. CAFs are a major component of the TME, providing physical support in it and secreting various proteins, such as extracellular matrices (ECMs), hepatocyte growth factor (HGF), insulin-like growth factor 1/2 (ILGF1/2) and cytokines that can modulate tumor growth and survival. As such, CAF-derived signaling may increase the pool of resistant cells, thus reducing the duration of clinical responses and increasing the degree of heterogeneity within tumors. Although CAFs are often implicated to be associated with tumor growth, metastasis and drug resistance, several studies have reported that CAFs have significant phenotypic and functional heterogeneity, and some CAFs display antitumor and drug-sensitizing properties. Multiple studies have highlighted the relevance of crosstalk between HCC cells, CAFs and other stromal cells in influence of HCC progression. Although basic and clinical studies partially revealed the emerging roles of CAFs in immunotherapy resistance and immune evasion, a better understanding of the unique functions of CAFs in HCC progression will contribute to development of more effective molecular-targeted drugs. In this review article, molecular mechanisms involved in crosstalk between CAFs, HCC cells and other stromal cells, as well as the effects of CAFs on HCC-cell growth, metastasis, drug resistance and clinical outcomes, are comprehensively discussed.

Integrated analysis of single-cell and bulk RNA sequencing data reveals a CD8+ T cells signature predicting prognosis and immunotherapy response in hepatocellular carcinoma

“…As a new favorite of cancer treatment, immunotherapy has played a signi cant role in a variety of solid tumors [36]. However, only some patients can bene t from this, and immunotherapy resistance and high treatment costs limit such technology in clinical application [37]. Accurate identi cation of patients with HCC who are sensitive to immunotherapy will greatly improve the clinical bene t of patients.…”

The role of alpha-fetoprotein in the tumor microenvironment of hepatocellular carcinoma

“…They promote HCC growth and drug resistance. They mediate HCC progression by activating signaling pathways, such as the JAK/STAT, MAPK, and Wnt/β-catenin pathways ( 61 ). AFP also activates these signaling pathways to promote the malignant transformation of cancer cells.…”

Targeting YAP1 to improve the efficacy of immune checkpoint inhibitors in liver cancer: mechanism and strategy

“…As an essential stromal cell in TME, CAFs are closely associated with the onset and progression of HCC. CAFs provide physical support for TME and secret proteins such as hepatocyte growth factor (HGF), and insulin-like growth factor-1/2 (IGF-1/2), among others in extracellular matrix (ECM) ( 87 ). HCC cells promote CAF proliferation, CAFs also promote the development and metastasis of HCC cells ( 88 , 89 ).…”