Cancer-Associated Fibroblasts in Hepatocellular Carcinoma and Cholangiocarcinoma

Abstract

Primary liver cancer (PLC) includes hepatocellular carcinoma and intrahepatic cholangiocarcinoma and is the sixth most common cancer worldwide with poor prognosis. PLC is characterized by an abundant stromal reaction in which cancer-associated fibroblasts (CAFs) are one of the major stromal components. Solid evidence has demonstrated the crucial role of CAFs in tumor progression, and CAF abundance is often correlated with poor clinical outcomes. Although CAFs are regarded as an attractive and promising target for PLC treatment, a poor understanding of CAF origins and heterogeneity and a lack of specific CAF markers are the major hurdles to efficient CAF-specific therapy. In this review, we examine recent advances in the understanding of CAF diversity in the context of biomarkers, subtypes, and functions in PLC. The regulatory roles of CAFs in extracellular matrix remodeling, metastasis, cancer stemness, and therapeutic resistance are summarized. With an increasing link between CAF abundance and reduced antitumor immune responses, we provide updated knowledge on the crosstalk between CAFs and immune cells within the tumor microenvironment, which leads to immune resistance. In addition, we present current CAF-targeted therapies and describe some future perspectives. A better understanding of CAF biology will shed light on a novel therapeutic strategy against PLC.

Keywords: Cancer-Associated Fibroblasts; Cholangiocarcinoma; Hepatocellular Carcinoma; Immune Suppression; Origin; Primary Liver Cancer.

Figure 1

Overview of the cellular origins of CAFs in HCC and CCA. CAFs can originate from multiple cell types including HSCs, PFs, fibrocytes, EMT, mesothelial cells, MSCs, and peritumoral fibroblasts. Several factors and exosome miRNA were reported as the drivers of those transdifferentiations.

Figure 2

CAFs and their secretome remodel the stromal environment and support immune evasion, metastasis, and stemness acquisition of PLC. Secretory functions of CAFs regulate ECM remodeling (top left); tumor immunity (bottom left); metastatic dissemination (top right); and self-renewal, tumor-initiating, and drug resistance capacities (bottom right) of PLC cells. CAFs secrete ECM proteins that contribute to matrix degradation, deposition, and stiffness (top left). ECM protein is also required to drive HSCs transdifferentiate into CAFs. ECM degradation and alignment of collagen fiber as alternative mechanisms in ECM remodeling could help to deliver CAF-promoting factors and results in CAFs activation. As a feedback loop, the activated CAFs could guide the cancer cells via alignment of collagen fiber for migration. In PLC TME, CAFs release various cytokines to tumor stroma, directly or indirectly foster immune cell infiltration, and polarize them to inhibitory subtypes, thus generating an environment favorable for tumor propagation (bottom left). CAF secretome also actively engages in HCC aggressive behaviors and metastatic colonization in lung, predominantly by inducing stemness features in HCC cells (top and bottom right). CAF mediators directly enhance renewal, tumorigenic, and therapeutic resistance properties in HCC cells, and indirectly promote these characteristics in iCCA cells in an MDSC-dependent manner (bottom right).