Review
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 21, 2019; 25(19): 2279-2293
Published online May 21, 2019. doi: 10.3748/wjg.v25.i19.2279
Mechanisms of hepatocellular carcinoma progression
Olorunseun O Ogunwobi, Trisheena Harricharran, Jeannette Huaman, Anna Galuza, Oluwatoyin Odumuwagun, Yin Tan, Grace X Ma, Minhhuyen T Nguyen
Olorunseun O Ogunwobi, Trisheena Harricharran, Jeannette Huaman, Anna Galuza, Oluwatoyin Odumuwagun, Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, United States
Olorunseun O Ogunwobi, Trisheena Harricharran, Jeannette Huaman, The Graduate Center Departments of Biology and Biochemistry, The City University of New York, New York, NY 10016, United States
Olorunseun O Ogunwobi, Trisheena Harricharran, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065, United States
Olorunseun O Ogunwobi, Trisheena Harricharran, Jeannette Huaman, Anna Galuza, Oluwatoyin Odumuwagun, Hunter College Center for Cancer Health Disparities Research (CCHDR), New York, NY 10065, United States
Yin Tan, Grace X Ma, Center for Asian Health, School of Medicine, Temple University, Philadelphia, PA 19140, United States
Minhhuyen T Nguyen, Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, United States
Author contributions: All authors contributed intellectually to this manuscript. Ogunwobi OO conceived, designed, revised, edited, and approved the final version of the manuscript.
Conflict-of-interest statement: Ogunwobi OO, Tan Y and Ma GX are supported by the National Cancer Institute grant number U54 CA221704(5). Ogunwobi OO is a Co-Founder of NucleoBio, Inc, a City University of New York biotechnology start-up company.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Olorunseun O Ogunwobi, MBBS, MSc, PhD, Associate Professor, Department of Biological Sciences, Hunter College of The City University of New York, 695 Park Ave, New York, NY 10065, United States. ogunwobi@genectr.hunter.cuny.edu
Telephone: +1-212-896-0447
Received: March 8, 2019
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
Abstract

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.

Keywords: Hepatocellular carcinoma, Viral/non-viral hepatitis, Alcohol consumption, Epithelial-mesenchymal transition, Tumor-stromal interactions, Tumor microenvironment, Cancer stem cells, Circulating tumor cells, Immunomodulation, Neural regulation

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.