Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a lethal disease, and recurrence and metastasis are the major causes of death in HCC patients. Cancer-associated fibroblasts (CAFs), a major stromal cell type in the HCC microenvironment, promote HCC progression, and have gradually become a hot research topic in HCC-targeted therapy. This review comprehensively describes and discusses the heterogeneous tissue distribution, cellular origin, phenotype, and biological functions of HCC-associated fibroblasts. Furthermore, the possible use of CAFs for predicting HCC prognosis and in targeted therapeutic strategies is discussed, highlighting the critical roles of CAFs in HCC progression, diagnosis, and therapy.

The Crosstalk between Tumor Cells and the Microenvironment in Hepatocellular Carcinoma: The Role of Exosomal microRNAs and Their Clinical Implications

“…The activated fibroblasts in the TME are named as cancer-associated fibroblasts (CAFs), and are the main source of collagen-producing cells, expressing α-smooth muscle actin (α-SMA), fibroblast activation protein (FAP), vimentin, and fibroblast-specific protein 1 (FSP-1). They represent the major stromal cell type with multiple roles in influencing tumor cell proliferation, migration, invasion, angiogenesis, immune escape, and drug resistance through an extended network of intercellular communication with tumor cells and other stromal cells [29].…”

“…CAFs are unique reprogrammed stromal cells with roles in cancer initiation, extracellular matrix remodeling, progression, pre-metastatic niche formation, and metastasis. CAFs secrete different tumor-supportive growth factors and nutrients to support cancer growth; in addition, they regulate the inflammatory environment during tumorigenesis [29,85]. In HCC, their origin remains controversial, as they can derive from activated hepatic stellate cells (HSC), from portal fibroblasts, or from transdifferentiation of hepatocytes through EMT, showing different phenotypes and biological function [29].…”

“…CAFs secrete different tumor-supportive growth factors and nutrients to support cancer growth; in addition, they regulate the inflammatory environment during tumorigenesis [29,85]. In HCC, their origin remains controversial, as they can derive from activated hepatic stellate cells (HSC), from portal fibroblasts, or from transdifferentiation of hepatocytes through EMT, showing different phenotypes and biological function [29]. HCC cell-derived exosomes activate human stellate cell line LX2, improving their proliferation and migration.…”

“…The interaction between tumor cells and stromal cells is understood as one of the determinant factors in the occurrence of metastasis [100]. Several stromal cells such as CAFs, mesenchymal stem cells (MSC), TAMs, and others can be involved in this process by releasing cytokines and exosomes that trigger cell proliferation, EMT, and the remodeling of the extracellular matrix [29,100]. CAFs also induce an inflammatory process in TME and inhibit the activity of cytotoxic T lymphocytes [29,101].…”

“…Several stromal cells such as CAFs, mesenchymal stem cells (MSC), TAMs, and others can be involved in this process by releasing cytokines and exosomes that trigger cell proliferation, EMT, and the remodeling of the extracellular matrix [29,100]. CAFs also induce an inflammatory process in TME and inhibit the activity of cytotoxic T lymphocytes [29,101]. In this scenario, exosomal miRNAs seem to play relevant roles as metastasis-promoting factors.…”