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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Oct 15, 2015; 7(10): 184-203
Published online Oct 15, 2015. doi: 10.4251/wjgo.v7.i10.184
Role of retinoids in the prevention and treatment of colorectal cancer
Catherine C Applegate, Michelle A Lane
Catherine C Applegate, Michelle A Lane, School of Family and Consumer Sciences, Nutrition and Foods Program, Texas State University, San Marcos, TX 78666, United States
Author contributions: Applegate CC and Lane MA jointly wrote this paper and contributed equally to this work.
Conflict-of-interest statement: Neither Catherine C Applegate nor Michelle A Lane have any conflicts of interest related to this manuscript. Neither author has received fees for serving as a speaker, a consultant, or an advisory board member. Michelle A Lane has research funding from Texas State University and the Heather Custer Memorial Fund. Both authors are employees of Texas State University. Michelle A Lane has a diversified stock portfolio as part of her retirement plan offered by her employer, Texas State University. These stocks/shares do not present a conflict of interest. Neither author owns a patent.
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: Michelle A Lane, PhD, Associate Professor, School of Family and Consumer Sciences, Nutrition and Foods Program, Texas State University, FCS Building, 601 University Drive, San Marcos, TX 78666, United States. ml48@txstate.edu
Telephone: +1-512-2454654 Fax: +1-512-2453829
Received: April 24, 2015
Peer-review started: April 24, 2015
First decision: June 1, 2015
Revised: June 10, 2015
Accepted: September 10, 2015
Article in press: September 16, 2015
Published online: October 15, 2015
Processing time: 178 Days and 10.3 Hours
Abstract

Vitamin A and its derivatives, retinoids, have been widely studied for their use as cancer chemotherapeutic agents. With respect to colorectal cancer (CRC), several critical mutations dysregulate pathways implicated in progression and metastasis, resulting in aberrant Wnt/β-catenin signaling, gain-of-function mutations in K-ras and phosphatidylinositol-3-kinase/Akt, cyclooxygenase-2 over-expression, reduction of peroxisome proliferator-activated receptor γ activation, and loss of p53 function. Dysregulation leads to increased cellular proliferation and invasion and decreased cell-cell interaction and differentiation. Retinoids affect these pathways by various mechanisms, many involving retinoic acid receptors (RAR). RAR bind to all-trans-retinoic acid (ATRA) to induce the transcription of genes responsible for cellular differentiation. Although most research concerning the chemotherapeutic efficacy of retinoids focuses on the ability of ATRA to decrease cancer cell proliferation, increase differentiation, or promote apoptosis; as CRC progresses, RAR expression is often lost, rendering treatment of CRCs with ATRA ineffective. Our laboratory focuses on the ability of dietary vitamin A to decrease CRC cell proliferation and invasion via RAR-independent pathways. This review discusses our research and others concerning the ability of retinoids to ameliorate the defective signaling pathways listed above and decrease tumor cell proliferation and invasion through both RAR-dependent and RAR-independent mechanisms.

Keywords: Colorectal cancer; Retinoid; Vitamin A; β-catenin; Phosphatidylinositol-3-kinase; K-ras; Cyclooxygenase-2; Peroxisome proliferator-activated receptor γ; P53; Phosphatase and tensin homolog deleted on chromosome 10

Core tip: Vitamin A and its derivatives, the retinoids, have been widely studied in many types of cancer for their ability to increase cell differentiation and decrease cell proliferation. This review focuses on the ability of retinoids to affect signaling pathways commonly disrupted in colorectal cancer. We discuss vitamin A metabolism and signaling, how this process becomes aberrant as colorectal cancer progresses, and how treatment with both dietary vitamin A and exogenous retinoids can alter these dysregulated signaling pathways to decrease colorectal cancer cell proliferation and invasion.