The Role of Cancer-Associated Fibroblasts and Fibrosis in Liver Cancer

Abstract

Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix—associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.

Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances

“…Emerging data implicates the desmoplastic reaction in iCCA as playing an active and crucial role in promoting progressive iCCA invasive growth and metastasis, CCA cell survival, resistance to chemotherapy and targeted agent therapies, and immunosuppression. (13,14) Underlying this relationship between the desmoplastic reaction and increased malignant behavior is the deleterious interplay between accumulating numbers of α-SMA+CAFs (and other stromal cell types), ECM proteins, and CCA cells interacting to fuel malignant aggressiveness and therapeutic resistance. (15) A comprehensive discussion of the complex cellular and molecular events that provoke, sustain, and remodel the desmoplastic stroma in iCCA is beyond the scope of this review.…”

Preclinical Models for Studying NASH-Driven HCC: How Useful Are They?

“…Nonetheless, the mechanisms by which fibrosis, which usually refers to the deposition of collagen fibers, affects HCC development are obscure. Furthermore, the cells that are responsible for collagen deposition in the liver, hepatic stellate cells (HSC), are related to activated myofibroblasts or cancer-associated fibroblasts (CAF), which are known to have broad-spectrum tumor-promoting activities, not all of which are related to collagen deposition (Affo et al, 2017). Activated HSC and CAF produce TGF-β and many other cytokines and chemokines that recruit follicular helper (T FH ) cells and naive B cells into the liver and stimulate conversion of the latter to immunosuppressive IgA + plasma cells, which accumulate in human NASH and promote NASH to HCC progression in mice (Shalapour et al, 2017).…”

Up‐regulation of ZFAS1 indicates dismal prognosis for cholangiocarcinoma and promotes proliferation and metastasis by modulating USF1 via miR‐296‐5p

“…Cholangiocarcinoma (CCA) is an aggressive epithelial carcinoma originates from the biliary ducts and the second most common malignancy of primary hepatobiliary tumours with an increasing morbidity worldwide . For instance, the incident of CCA reaches a number of approximately 7500 each year in the USA .…”