Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever

Abstract

, cyclin-dependent kinase inhibitor; PAI-1, plasminogen activator inhibitor-1; PDGF, platelet-derived growth factor; TGF, transforming growth factor; a-SMA, alpha-smooth muscle actin.Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third leading cause of cancer death. Recent epidemiological data indicate that the mortality rate of HCC will double over the next decades in the USA and Europe. Liver cancer progresses in a large percentage of cases during the clinical course of chronic fibro-inflammatory liver diseases leading to cirrhosis. Therefore, HCC development is regarded as the result of different environmental risk factors each involving different genetic, epigenetic-and chromosomal alterations and gene mutations. During tumour progression, the malignant hepatocytes and the activated hepatic stellate cells are accompanied by cancer-associated fibroblasts, myofibroblasts and immune cells generally called tumour stromal cells. This new and dynamic milieu further enhances the responsiveness of tumour cells towards soluble mediators secreted by tumour stromal cells, thus directly affecting the malignant hepatocytes. This results in altered molecular pathways with cell proliferation as the most important mechanism of liver cancer progression. Given this contextual complexity, it is of utmost importance to characterize the molecular pathogenesis of HCC, and to identify the dominant pathways/ drivers and aberrant signalling pathways. This will allow an effective therapy for HCC that should combine strategies affecting both cancer and the tumour stromal cells. This review provides an overview of the recent challenges and issues regarding hepatic stellate cells, extracellular matrix dynamics, liver fibrosis/cirrhosis and therapy, tumour microenvironment and HCC.

CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression

“…These lesions can progress to dysplastic nodules, which have abnormal chromosome features including numerical and structural alterations. These dysplastic nodules can evolve to HCC marked with recurrent regions of copy number change and allelic imbalances 3 4. Loss of certain tumour suppressors or gain of specific oncogenes promote cell division as shown in many previous studies 25 32.…”

“…Different aetiological factors such as hepatitis B and C virus, alcohol and diabetes cause liver injury followed by inflammation, necrosis and hepatocytes proliferation 2. Continuous cycles of this destructive–regenerative process culminates in liver cirrhosis which is characterised by regenerating nodules that progress to dysplastic nodules and ultimately HCC 3 4. More than 90% of HCC, including dysplastic nodules in cirrhotic liver, possess chromosomal aberrations suggesting that chromosomal defects occur at early stages of tumour development and several attempts have been made to connect different chromosomal aberration patterns as specific subsets of HCC, although with limited success 5–7.…”

Study on the effects of blueberry treatment on histone acetylation modification of CCl₄-induced liver disease in rats

“…Hepatocyte injury and necrosis are used to induce the aggregation, activation and release of inflammatory cells, which in turn causes large amounts of extracellular matrix (ECM) to be present in the liver, leading to the development of hepatic fibrosis (Sato et al, 2003;Carloni et al, 2014). This also corresponds to intermediate links in the development of the "chronic liver disease-liver fibrosis-cirrhosis" model (Das and Vasudevan, 2008).…”

Hepatocellular carcinoma treatment over sorafenib: epigenetics, microRNAs and microenvironment. Is there a light at the end of the tunnel?

“…During hepatic inflammation, HSCs undergo a transformation from quiescent cells towards 'activated' myofibroblast-like cells, with proliferative stimuli. Moreover, HSCs secrete several proteases, tumor growth and pro-angiogenic factors [114]. In vitro and in vivo studies show that HSCs can directly influence HCC cells and create an immunosuppressive environment that promotes liver fibrosis and HCC cell growth [115,116].…”