Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 14, 2023; 29(18): 2764-2783
Published online May 14, 2023. doi: 10.3748/wjg.v29.i18.2764
Wingless/It/β-catenin signaling in liver metastasis from colorectal cancer: A focus on biological mechanisms and therapeutic opportunities
Federico Selvaggi, Teresa Catalano, Rossano Lattanzio, Roberto Cotellese, Gitana Maria Aceto
Federico Selvaggi, Department of Surgical, ASL2 Lanciano-Vasto-Chieti, Ospedale Clinicizzato SS Annunziata of Chieti, Chieti 66100, Italy
Teresa Catalano, Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
Rossano Lattanzio, Department of Innovative Technologies in Medicine & Dentistry, University “G. d’Annunzio” Chieti-Pescara, Chieti 66100, Italy
Roberto Cotellese, Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Chieti 66100, Italy
Roberto Cotellese, Villa Serena Foundation for Research, Villa Serena - Del Dott. L. Petruzzi, Città Sant’Angelo 65013, Pescara, Italy
Gitana Maria Aceto, Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
Author contributions: Aceto GM conceptualized and designed the study; Selvaggi F and Aceto GM developed the first draft, refined, edited, and revised the manuscript; Catalano T, Lattanzio R and Cotellese R contributed to the content materials and final editing; Aceto GM and Selvaggi F designed the images.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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:
Corresponding author: Gitana Maria Aceto, MSc, PhD, Research Scientist, Senior Lecturer, Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini, Chieti 66100, Italy.
Received: January 23, 2023
Peer-review started: January 23, 2023
First decision: February 7, 2023
Revised: February 28, 2023
Accepted: April 17, 2023
Article in press: April 17, 2023
Published online: May 14, 2023

The liver is the most common site of metastases in patients with colorectal cancer. Colorectal liver metastases (CRLMs) are the result of molecular mechanisms that involve different cells of the liver microenvironment. The aberrant activation of Wingless/It (Wnt)/β-catenin signals downstream of Wnt ligands initially drives the oncogenic transformation of the colon epithelium, but also the progression of metastatization through the epithelial-mesenchymal transition/mesenchymal-epithelial transition interactions. In liver microenvironment, metastatic cells can also survive and adapt through dormancy, which makes them less susceptible to pro-apoptotic signals and therapies. Treatment of CRLMs is challenging due to its variability and heterogeneity. Advances in surgery and oncology have been made in the last decade and a pivotal role for Wnt/β-catenin pathway has been re-cognized in chemoresistance. At the state of art, there is a lack of clear understanding of why and how this occurs and thus where exactly the opportunities for developing anti-CRLMs therapies may lie. In this review, current knowledge on the involvement of Wnt signaling in the development of CRLMs was considered. In addition, an overview of useful biomarkers with a revision of surgical and non-surgical therapies currently accepted in the clinical practice for colorectal liver metastasis patients were provided.

Keywords: Wingless/It/β-catenin signaling, Colorectal cancer, Epithelial-mesenchymal transition/ mesenchymal-epithelial transition, Liver metastasis, Markers, Surgical and non-surgical therapies

Core Tip: The liver is the most common site of metastasis in patients with colorectal cancer. Wingless/It (Wnt)/β-catenin signals can drive progression and metastatization by epithelial-mesenchymal transition/mesenchymal-epithelial transition. In the hepatic microenvironment, metastatic cells can survive through dormancy and become refractory to therapy. Further studies are needed to elucidate involvement of Wnt signaling in the development of colorectal liver metastases and to improve current surgical and non-surgical therapeutic approaches.