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Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Dec 24, 2021; 12(12): 1101-1156
Published online Dec 24, 2021. doi: 10.5306/wjco.v12.i12.1101
Liver regeneration biology: Implications for liver tumour therapies
Christopher Hadjittofi, Michael Feretis, Jack Martin, Simon Harper, Emmanuel Huguet
Christopher Hadjittofi, Michael Feretis, Jack Martin, Simon Harper, Emmanuel Huguet, University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
Author contributions: Hadjittofi C authored text in sections on animal and in vitro models, and alternative regeneration pathways; Feretis M authored text in sections on in vitro and human models; Martin J authored text in sections on zebrafish models; Hadjittofi C, Feretis M and Martin J complex mitogens; Harper S assisted in design of manuscript and manuscript review; Huguet E designed the structure of the overall manuscript and authored text in all sections; all authors have read and approved the final manuscript.
Conflict-of-interest statement: No conflict of interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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: Emmanuel Huguet, BSc, DPhil, FRCS, MBChB, Surgeon, Surgical Oncologist, University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, United Kingdom. emmanuel.huguet@addenbrookes.nhs.uk
Received: April 27, 2021
Peer-review started: April 28, 2021
First decision: June 16, 2021
Revised: June 20, 2021
Accepted: November 26, 2021
Article in press: November 26, 2021
Published online: December 24, 2021
Processing time: 241 Days and 2.5 Hours
Abstract

The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.

Keywords: Liver; Liver regeneration potential; Regeneration biology; Tumour; Therapies

Core Tip: The liver has remarkable regenerative potential, allowing recovery from 90% hepatectomy in some rodent models. Current understanding of liver regeneration comes from in vitro and animal models. Liver regeneration is controlled by mitogens acting in autocrine, paracrine, and endocrine ways. Complex cross talk occurs between parenchymal and non-parenchymal cells. Regeneration involves hypertrophy and hyperplasia, with both cellular phenotypic fidelity and transdifferentiation, which come into play according to the nature and magnitude of the injury, and the presence of underlying liver disease. Current knowledge provides guiding principles for strategies to optimise liver regeneration potential in the treatment of liver tumours.