Origin and role of hepatic myofibroblasts in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)-and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.

Complex Tumor Spheroid Formation and One-Step Cancer-Associated Fibroblasts Purification from Hepatocellular Carcinoma Tissue Promoted by Inorganic Surface Topography

“…Farther from the contact area, the cell layer consisted mainly of invading CAFs. If the peri-tumoral piece was removed, the cell layer consisted exclusively of fibroblast with a low signal of α-SMAm, which is an indicator for modified fibroblasts [1,55]. As expected, the residual cells from the tumor piece consisted of AFP-positiv which were localized with the highest concentration to the contact area of the tum topographic surface (arrow in Figure 5a).…”

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

“…The high abundance of α-SMA positive periductal cells found in Mdr2 -KO mice [ 65 ] was also markedly reduced by CM414 treatment ( Figure 3 d). In response to the cholestatic injury, portal fibroblasts, which reside around the portal area and maintain the integrity of the biliary tree and portal tract, proliferate, get activated, and together with hepatic stellate cells, contribute to collagen type I deposition [ 66 ]. CD34, a marker of portal fibroblasts [ 62 ], was found highly expressed in control Mdr2 -KO mice, predominantly in the portal and sinusoidal areas ( Figure 3 d).…”

The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer

“…Therefore, considering that HSCs are the main cell type responsible for ECM deposition and liver fibrosis, this suggests that HSCs may play an important role in tumour formation and development. For instance, activated HSCs promote HCC progression through the secretion of a large panel of cytokines, depending on the aetiology of the liver fibrosis [97].…”