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
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Shirin R. Modarai1,2, Anindita Gupta1,2, Lynn M. Opdenaker1,2, Ryan Kowash2,3, Gabriel Masters2,4, Vignesh Viswanathan1,2, Tao Zhang1,2,5,6, Jeremy Z. Fields7 and Bruce M. Boman1,2,5
1Department of Biological Sciences, University of Delaware, Newark, DE, USA
2Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, Newark, DE, USA
3Department of Biological Sciences, Dickinson College, Carlisle, PA, USA
4Biochemistry Department, Hamilton College, Clinton, NY, USA
5Genetic and Preventive Medicine, Thomas Jefferson University, Philadelphia, PA, USA
6Research Pediatric Development, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
7Cancer Research, CATX Inc., Gladwyne, PA, USA
Bruce M. Boman, email: [email protected]
Keywords: ALDH; retinoic acid; colorectal cancer; stem cell; neuroendocrine cell
Received: August 09, 2018 Accepted: August 15, 2018 Published: October 05, 2018
Background: Tumorigenesis 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.
Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonic SCs; dysregulation of RA signaling contributes to SC overpopulation and colorectal cancer (CRC) development.
Methods: We 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.
Results: RXR & 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.
Conclusions: Retinoid 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.
Implications: That 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.
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