The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells.

Shirin R Modarai,Vignesh Viswanathan,Jeremy Z Fields,Lynn M Opdenaker,Anindita Gupta,Bruce M Boman,Tao Zhang,Ryan Kowash,Gabriel Masters

doi:10.18632/oncotarget.26157

Shirin R Modarai, Vignesh Viswanathan + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.26157

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Abstract

BackgroundTumorigenesis is driven by stem cell (SC) overpopulation. Because ALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA) signaling, we studied RA signaling in normal and malignant colonic SCs.HypothesisRA signaling regulates growth and differentiation of ALDH+ colonic SCs; dysregulation of RA signaling contributes to SC overpopulation and colorectal cancer (CRC) development.MethodsWe analyzed normal and malignant colonic tissues and CRC cell lines to see if retinoid receptors (RXR & RAR) are exclusively expressed in ALDH+ SCs, and if RA signaling changes during CRC development. We determined whether RA signaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation, and population size.ResultsRXR & RAR were expressed in ALDH+ colonic SCs, but not in MCM2+ proliferative cells. Western blotting/immunostaining of CRCs revealed that RA signaling components become overexpressed in parallel with ALDH overexpression, which coincides with the known overpopulation of ALDH+ SCs that occurs during, and drives, CRC development. Treatment of SCs with all-trans retinoic acid (ATRA) decreased proliferation, sphere formation and ALDH+ SC population size, and induced differentiation along the neuroendocrine cell (NEC) lineage.ConclusionsRetinoid signaling, by regulating ALDH+ colonic CSCs, decreases SC proliferation, sphere formation, and population size, and increases SC differentiation to NECs. Dysregulation of RA signaling in colonic SCs likely contributes to overpopulation of ALDH+ SCs and CRC growth.ImplicationsThat retinoid receptors RXR and RAR are selectively expressed in ALDH+ SCs indicates RA signaling mainly occurs via ALDH+ SCs, which provides a mechanism to selectively target CSCs.

Highlights

Stem cell (SC) overpopulation drives colorectal cancer (CRC) development and growth
Western blotting/immunostaining of CRCs revealed that retinoid acid (RA) signaling components become overexpressed in parallel with aldehyde dehydrogenase (ALDH) overexpression, which coincides with the known overpopulation of ALDH+ stem cell (SC) that occurs during, and drives, CRC development
Implications: That retinoid receptors retinoic X receptor (RXR) and retinoic acid receptor (RAR) are selectively expressed in ALDH+ SCs indicates RA signaling mainly occurs via ALDH+ SCs, which provides a mechanism to selectively target cancer SC (CSC)

Summary

Introduction

Stem cell (SC) overpopulation drives colorectal cancer (CRC) development and growth. Because aberrant regulation of SC dynamics likely contributes to SC overpopulation, understanding how colon SCs are regulated is important [1]. Because ALDH is a key enzyme in the retinoic acid (RA) signaling pathway, and because aberrant RA signaling alters cell proliferation and differentiation that contributes to CRC progression [3,4,5], we studied RA signaling in normal and malignant colon SCs. Our long-term goal was to determine how RA signaling regulates SC dynamics and how dysregulation of RA signaling leads to CRC initiation and progression. Because ALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA) signaling, we studied RA signaling in normal and malignant colonic SCs. Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonic SCs; dysregulation of RA signaling contributes to SC overpopulation and colorectal cancer (CRC) development

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