Abstract
Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis.
Highlights
As declared by the WHO (World Health Organization) Global Hepatitis Report [1], hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the second most common cause of death related to cancer in the last years
If on the one hand it has been shown that patients with non-alcoholic steatohepatitis (NASH) can develop HCC in the absence of fibrosis or cirrhosis [6,7], on the other, it is shown that fibrosis plays a crucial role in causing HCC and its presence is correlated with poor prognosis [8,9]
NASH is a complex and extremely heterogeneous metabolic disease and despite several mouse models can mimic disease; rarely, they replicate the pathogenic sequence of human NASH-HCC
Summary
As declared by the WHO (World Health Organization) Global Hepatitis Report [1], hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the second most common cause of death related to cancer in the last years. The main risk factors are chronic HBV and HCV infection, NAFLD/NASH, alcoholic hepatitis, and any disease leading to cirrhosis. HCC development is considered as result of different environmental risk factors that engage distinct genetic, epigenetic, and chromosomal alterations. It originates from chronic liver injury through a complex multistep process that involves several pathogenic mechanisms that contribute to carcinogenesis [11]. To overcome this problem, reproducible and representative preclinical models that are susceptible to genetic and functional analysis are used. In this review we will discuss the latest findings on the pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH and their potential therapeutic targets
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