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.

An HCC Aggressiveness Index and Blood GTP, Bilirubin and Platelet Levels

“…It has long been accepted that growing HCC tumor masses can destroy or replay liver parenchyma and thus enhance liver damage. There is now evidence that the converse is also likely true and that liver micro environmental factors may influence HCC growth and invasion [12][13][14][15][16][17][18][19]. Molecular signatures of the underlying liver in HCC patients provide support for this idea [25][26][27], as well as recently reported clinical associations of changes in liver function with HCC biology [3].…”

“…As a result, elements of both sets of factors are included in most HCC classification and prognostication systems [10] with increasing refinements [11]. The underlying liver has been increasingly understood as a complex dynamic of cells, tissues, inflammatory cytokines and growth factors [12][13][14][15][16][17][18]. This has been most extensively studied with respect to the neo vascular endothelial cells that form the blood vessels that are needed to support the growing tumor mass, and are an important target for various multikinase inhibitors, which are used in cancer therapy.…”

Heterogeneity of liver cancer and personalized therapy

“…Once the normal microenvironment is disrupted, diseases can rapidly progress. The elements of the liver microenvironment which have been certified to play a pivotal role in HCC propensity, progression and treatment response are as follows: immune cells, stellate cells, hepatitis viruses, abnormal extracellular matrix (ECM), tissue hypoxia and the newly recognized factors including diet, gastrointestinal tract microflora and circulating microvesicles [58].…”

Novel insights into the function and dynamics of extracellular matrix in liver fibrosis

“…Similarly, HCC prevalence and progression is related to cirrhosis (93) in alcoholic steatohepatitis and NASH (8), with a yearly HCC incidence of 1.7% (93) and 2.6%, respectively (8). Mechanisms linking fibrosis and HCC are in need of further exploration, whereas there is increasing evidence that the fibrotic/cirrhotic and associated (immunosuppressive) inflammatory liver microenvironment appears to be a major player in HCC pathology, with several molecular pathways being shared between fibrogenesis and carcinogenesis (340). Thus, apart from direct carcinogens such as hepatitis B virus, microenvironmental stimuli include intrahepatic cell subpopulations, such as progenitor, immune and stellate cells, proliferative or differentiation-modulating cytokines, and growth factors like TGF-␤1, EGF, IGF-1, and VEGF and altered ECM molecules and ECM receptors like the integrins.…”