Novel aspects of the liver microenvironment in hepatocellular carcinoma pathogenesis and development

Abstract

Hepatocellular carcinoma (HCC) is a prevalent primary liver cancer that is derived from hepatocytes and is characterised by high mortality rate and poor prognosis. While HCC is driven by cumulative changes in the hepatocyte genome, it is increasingly recognised that the liver microenvironment plays a pivotal role in HCC propensity, progression and treatment response. The microenvironmental stimuli that have been recognised as being involved in HCC pathogenesis are diverse and include intrahepatic cell subpopulations, such as immune and stellate cells, pathogens, such as hepatitis viruses, and non-cellular factors, such as abnormal extracellular matrix (ECM) and tissue hypoxia. Recently, a number of novel environmental influences have been shown to have an equally dramatic, but previously unrecognized, role in HCC progression. Novel aspects, including diet, gastrointestinal tract (GIT) microflora and circulating microvesicles, are now being recognized as increasingly important in HCC pathogenesis. This review will outline aspects of the HCC microenvironment, including the potential role of GIT microflora and microvesicles, in providing new insights into tumourigenesis and identifying potential novel targets in the treatment of HCC.

Figure 1

A simplified network of liver microenvironmental factors and their roles in HCC tumour progression and maintenance. Established causal interactions between microenvironmental factors (italicised within the dashed circle) and HCC tumour progression and maintenance are represented by solid arrows, while dashed arrows are interactions that have not yet been conclusively shown. Some known interactions are not shown for clarity. In this review, we describe the direct effects of the liver microenvironment on this network (bold): chronic inflammation; tissue remodeling; genetic alterations; and altered cellular expression. ROS = Reactive Oxygen Species; HBV = Hepatitis B Virus; HCV = Hepatitis C virus; GIT = Gastrointestinal Tract; ECM = Extracellular Matrix.

Figure 2

A schematic diagram of interactions between the ECM and cells in the liver microenvironment.