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

Abstract

The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

“…Another major component of the tumor microenvironment are tumor-associated macrophages, which play a pivotal role HCC [ 119 , 120 ]. Macrophages are heterogeneous by nature, as they actively engage in both induction and resolution of inflammation.…”

Review article: vascular effects of PPARs in the context of NASH

“…88 The main mediator of vascular dilatation is NO, but the endothelial function is also sensitive to certain circulating factors, some of which are altered in the case of liver disease. 18 As detailed above, PPAR proteins are protective against endothelial dysfunction, in particular by promoting NO production. NO production is especially sensitive to oxidative stress, which is defined as an imbalance between the production of reactive oxygen species (ROS) and the antioxidant capacities of the cell.…”

“…In this healthy scenario, LSECs synthesise nitric oxide (NO) and other vasodilators that are detected by HSCs, which subsequently induces vasodilation. However, during chronic liver disease, LSECs lose their specialised phenotype and their ability to produce NO decreases, which altogether with the reduced sensitivity of HSCs to vasodilators leads to microvascular dysfunction 18 . Activated HSC in diseased liver responds by cell contraction and proliferation, which further affects intrahepatic blood flow.…”

“…The main mediator of vascular dilatation is NO, but the endothelial function is also sensitive to certain circulating factors, some of which are altered in the case of liver disease 18 . As detailed above, PPAR proteins are protective against endothelial dysfunction, in particular by promoting NO production.…”

“…In the normal liver, liver sinusoidal endothelial altogether with the reduced sensitivity of HSCs to vasodilators leads to microvascular dysfunction. 18 Activated HSC in diseased liver responds by cell contraction and proliferation, which further affects intrahepatic blood flow. These vascular abnormalities are known as the dynamic component of the increased intrahepatic vascular resistance in liver disease, being the primary factor in the development of portal hypertension.…”