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.

Keywords: cancer-associated fibroblasts; crosstalk; hepatocellular carcinoma; tumor microenvironment; tumor-associated neutrophils.

Figure 1

Epithelial cells, mesothelial cells, resident fibroblasts, pancreatic and hepatic stellate cells, pericytes, adipocytes, mesenchymal stem cells, myeloid cells and endothelial cells have been reported as potential cellular origins of cancer-associated fibroblasts (CAFs).

Figure 2

This figure indicates the mechanisms involved in cancer-associated fibroblast (CAF) activation. FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; TGFβ, transforming growth factor β; TNF, tumor necrosis factor.

Figure 3

This figure indicates potential cells from which cancer-associated fibroblasts (CAFs) originate in HCC: HCC cells, Mesenchymal stem cells, hepatic stellate cells, resident fibroblasts, hepatocytes, endothelial cells, cancer-derived exosomes and epithelial cells.

Figure 4

This figure indicates cancer-associated fibroblast functions and the mechanisms that regulate them. Lines connect mechanisms to functions. Both matrix remodeling and production of soluble factors promote tumor-cell invasion. Soluble factors also play a critical role in tumor-cell growth and changes in tumor microenvironments, which are also influenced by the altered metabolic states of tumors. CAF, cancer-associated fibroblast; CCL2, CC-chemokine ligand 2; CXCL12, CXC-chemokine ligand 12; IL-6, interleukin 6; GAS6, growth arrest-specific protein 6; HGF, hepatocyte growth factor; TGFβ, transforming growth factor-β; VEGF, vascular endothelial growth factor.