Published online May 21, 2019. doi: 10.3748/wjg.v25.i19.2279
Peer-review started: March 8, 2019
First decision: March 20, 2019
Revised: March 27, 2019
Accepted: April 10, 2019
Article in press: April 10, 2019
Published online: May 21, 2019
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.
Core tip: The overall prognosis for hepatocellular carcinoma patients remains poor, as there has only been minimal improvement over the past 15 years. Details of the mechanisms of hepatocellular carcinoma progression remain unclear. This review discusses a summary of both well-established and newly proposed mechanisms of hepatocellular carcinoma progression. A better understanding of these mechanisms is critical to the development of novel and more effective therapeutic strategies likely to improve hepatocellular carcinoma patient outcomes.