Abstract
Retinoids are vitamin A metabolites best known for their role in embryonic development. Indeed, retinoid acid (RA) signaling plays a key role in regulating the development of the embryo body-plan by controlling embryonic stem cells (SCs). Retinoids function through their ability to induce cellular differentiation. Mutations in RA signaling pathway genes occur in most human cancers. The classic example is the chromosomal translocation involving RA receptor alpha in acute promyelocytic leukemia (APL). Because all-trans retinoic acid (ATRA) is a highly effective and often curative treatment for APL patients, determining if retinoids are efficacious for other cancer types is imperative. We review the current research on retinoids in colorectal cancer (CRC) and provide bioinformatics analyses of RA signaling. Our results show that most RA pathway genes are overexpressed and often mutated in CRC. Moreover, aberrant expression of many RA signaling proteins predicts decreased CRC patient survival. We also review aldehyde dehydrogenase (ALDH) expression in CRC because ALDH is a key enzyme in RA signaling, which regulates colonic SCs. Further investigation of RA signaling mechanisms that regulate colon SCs and how dysregulation contributes to the SC overpopulation that drives CRC growth should provide insight into strategies for designing new SC-targeted therapies for CRC.
Highlights
Our goal is to review current research findings on retinoids in colorectal cancer (CRC), and to provide an update from our bioinformatics analysis of retinoid acid (RA) signaling components in CRC
Our results indicate that RA signaling, when dysregulated, plays a major role in the stem cells (SCs) origin of CRC
A few clues gleaned from our review are as follows: (i) drug screens using CRC cell lines (Table 1) and knockout of RA-signaling genes in human CRC cells might identify which retinoid drugs are active against cells with specific mutations; (ii) ApcMin/+ mice may be useful to identify additional retinoid agents that are active against Apc mutant tissues; (iii) strategies for designing retinoid-based CRC therapies will likely need to incorporate retinoids into drug combination regimens; (4) CRCs will likely need to be genotyped to determine the status of RA signaling genes when administering RA-based treatments to CRC patients
Summary
Our goal is to review current research findings on retinoids in colorectal cancer (CRC), and to provide an update from our bioinformatics analysis of RA signaling components in CRC. We discuss the anti-cancer activity of retinoids using in vitro and in vivo models of CRC, and the use of ATRA as a differentiation agent in SC research [4, 6–8]. A strong rationale to investigate RA signaling in oncology research is that ATRA is an effective drug used to treat APL patients. Current treatment regimens for APL include arsenic in combination with ATRA because the combination provides a synergic drug response that cures the majority of APL patients, who Colorectal Cancer would otherwise be facing a highly fatal illness. Future retinoid-based treatments for other cancers will likely necessitate drug combinations that incorporate a RA signaling differentiation therapy and a SC-targeting therapy that inhibits cancer SC self-renewal
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