The origins, roles and therapies of cancer associated fibroblast in liver cancer

Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. It is often preceded by chronic inflammation such as liver fibrosis and cirrhosis. Different cell types are believed to give rise to liver-specific cancer associated fibroblast (CAF), these include resident fibroblast, hepatic stellate cell, liver cancer cell, hepatic sinusoidal endothelial cell and mesenchymal stromal cell. The abundance of fibroblasts has contributed to the cancer progression, immune modulation and treatment resistance in HCC. In this review, we discussed the origins, subtypes and roles of cancer associated fibroblasts in HCC. Their specific roles in shaping the tumor microenvironment, facilitating cancer growth, and modulating different immune cell types to confer a permissive environment for cancer growth. CAF is now an attractive therapeutic target for cancer treatment, however specific therapeutic development in HCC is still lacking. Hence, we have included preclinical and clinical development of CAF-specific interventions for other cancer types in this review. However, most CAF-specific therapies have resulted in disappointing clinical outcomes, likely due to the difficulties in differentiating CAF from normal fibroblast. A thorough understanding of the characteristics and functionalities of CAF is warranted to further improve the therapeutic efficacy of anti-CAF therapies.

Tumor Microenvironment Remodeling in Gastrointestinal Cancer: Role of miRNAs as Biomarkers of Tumor Invasion

“…They originate predominantly from tissue-resident fibroblasts that are activated in response to signals from cancer cells and the TME [ 57 ]. In GI tumors, particularly in CRC and HCC, the presence of activated CAFs lead to increased expression of activated markers, such as α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP), and the production of large amounts of glycoproteins, including tenascin-C and collagen maturation enzymes, which are responsible for ECM remodeling [ 58 , 59 ]. Alterations in the biomechanical properties of the ECM can trigger cancer cell migration [ 53 , 60 ].…”

The tumor microenvironment in hepatocarcinoma: dissecting the functions of cancer-associated fibroblasts

“…In addition to Gas6, CAFs also overexpress the plasminogen activator inhibitor 1 (PAI 1), another mediator of the M1-M2 transdifferentiation [75] . Furthermore, this phenotypic shift can be induced by CAFs through the secretion of numerous other mediators, such as IL-6, IL-10, IL-13, and TGF-β [76,77] . Notably, the presence of M2 macrophages has a strong impact on several malignant features of HCC, such as cell proliferation, tendency to metastasis, and induction of stem-like signatures.…”