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World J Gastroenterol. Oct 28, 2018; 24(40): 4536-4547
Published online Oct 28, 2018. doi: 10.3748/wjg.v24.i40.4536
Dimensions of hepatocellular carcinoma phenotypic diversity
Romain Désert, Natalia Nieto, Orlando Musso
Romain Désert, Orlando Musso, Institut NuMeCan, Université de Rennes 1, Institut national de la recherche agronomique (INRA), Institut national de la santé et de la recherche médicale (INSERM), Rennes F-35000, France
Romain Désert, Natalia Nieto, Department of Pathology, Department of Medicine (Gastroenterology and Hepatology), University of Illinois at Chicago, IL 60612, United States
Author contributions: Désert R and Musso O designed research; Désert R, Nieto N and Musso O wrote and edited the manuscript; Désert R and Musso O designed figures and tables.
Supported by INSERM (to Musso O); United States Department of Defense Office of the Congressionally Directed Medical Research Programs Grant, No. CA170172 (to Nieto N and Désert R).
Conflict-of-interest statement: The authors have no conflict of interest to declare.
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/
Correspondence to: Orlando Musso, MD, PhD, Senior Scientist, U-1241 Institut NuMeCan, Université de Rennes 1, INRA, INSERM, Nutrition, Métabolismes et Cancer, Hôpital Pontchaillou, rue Henri Le Guilloux, Rennes F-35000, France. orlando.musso@inserm.fr
Telephone: +33-2-23234565 Fax: +33-2-99540137
Received: July 3, 2018
Peer-review started: July 4, 2018
First decision: August 1, 2018
Revised: August 31, 2018
Accepted: October 5, 2018
Article in press: October 5, 2018
Published online: October 28, 2018
Processing time: 118 Days and 14 Hours
Abstract

Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer-related death worldwide. More than 80% of HCCs arise within chronic liver disease resulting from viral hepatitis, alcohol, hemochromatosis, obesity and metabolic syndrome or genotoxins. Projections based on Western lifestyle and its metabolic consequences anticipate a further increase in incidence, despite recent breakthroughs in the management of viral hepatitis. HCCs display high heterogeneity of molecular phenotypes, which challenges clinical management. However, emerging molecular classifications of HCCs have not yet formed a unified corpus translatable to the clinical practice. Thus, patient management is currently based upon tumor number, size, vascular invasion, performance status and functional liver reserve. Nonetheless, an impressive body of molecular evidence emerged within the last 20 years and is becoming increasingly available to medical practitioners and researchers in the form of repositories. Therefore, the aim this work is to review molecular data underlying HCC classifications and to organize this corpus into the major dimensions explaining HCC phenotypic diversity. Major efforts have been recently made worldwide toward a unifying “clinically-friendly” molecular landscape. As a result, a consensus emerges on three major dimensions explaining the HCC heterogeneity. In the first dimension, tumor cell proliferation and differentiation enabled allocation of HCCs to two major classes presenting profoundly different clinical aggressiveness. In the second dimension, HCC microenvironment and tumor immunity underlie recent therapeutic breakthroughs prolonging patients’ survival. In the third dimension, metabolic reprogramming, with the recent emergence of subclass-specific metabolic profiles, may lead to adaptive and combined therapeutic approaches. Therefore, here we review recent molecular evidence, their impact on tumor histopathological features and clinical behavior and highlight the remaining challenges to translate our cognitive corpus into patient diagnosis and allocation to therapeutic options.

Keywords: Liver metabolism; Liver zonation; Hepatocellular carcinoma classification; Wnt/β-catenin; TP53; Tumor microenvironment; Inflammation; Tumor immunity; Hepatocyte proliferation; Hepatocyte differentiation

Core tip: Recent work revealed substantial steps toward a unifying molecular classification of human hepatocellular carcinomas. The expected translation of high-throughput assays to the clinical practice will further refine evidence-based patient management in terms of prognosis and response to treatment.