Abstract 2878: Anti-cancer effects of retinoic acid in CRC occurs via decreased growth of ALDH+ cancer stem cells and increased differentiation of stem cells to neuroendocrine cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.2878-2878
• Main Authors: Modarai, Shirin R., Opdenaker, Lynn M., Gupta, Anindita, Fields, Jeremy Z., Boman, Bruce M.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-2878

Our studies on tissues from colon cancer patients show that in the development of colorectal cancer (CRC), stem cell (SC) overpopulation underlies tumor initiation and progression. Because aldehyde dehydrogenase (ALDH) is a marker for SCs in several tissues and is a key enzyme in retinoid acid (RA) signaling, we investigated the role of RA signaling in normal and malignant colonic SCs. Our overall hypothesis is that RA signaling regulates growth and differentiation of ALDH+ colonic SCs and dysregulation of RA signaling contributes to SC overpopulation in CRC development. To begin to investigate underlying mechanisms, we analyzed CRC cell lines/tissues to see if retinoid receptors RXR and RAR are exclusively expressed in ALDH+ SCs and if the RA pathway components change during CRC development. We determined whether RA signaling influences SC proliferation, differentiation, self-renewal, and SC population size. RXR & RAR were selectively expressed in ALDH+ colonic SCs, but not in MCM2+ proliferative cells, suggesting that RA signaling mainly occurs in SCs. Western blotting/immunostaining of CRCs revealed that RA signaling components, including RAR and RXR, become overexpressed in parallel with ALDH overexpression, which coincides with the known overpopulation of ALDH+ SCs that occurs during CRC development. Treatment of cells with RA ligands (ATRA, 9-cis RA) inhibited proliferation, reduced sphere formation, decreased ALDH+ SC population size, and induced differentiation along the neuroendocrine cell (NEC) lineage. Taken together, our findings indicate that: (1) retinoid signaling, by regulating ALDH+ colonic SCs, reduces SC proliferation, self-renewal and SC population size, and promotes SC differentiation to NECs, and (2) dysregulation of RA signaling in colonic SCs likely contributes to overpopulation of ALDH+ SCs and CRC growth. Thus, RA signaling, by inducing increased differentiation of the SC population, suggests a novel therapeutic target. Citation Format: Shirin R. Modarai, Lynn M. Opdenaker, Anindita Gupta, Jeremy Z. Fields, Bruce M. Boman. Anti-cancer effects of retinoic acid in CRC occurs via decreased growth of ALDH+ cancer stem cells and increased differentiation of stem cells to neuroendocrine cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2878. doi:10.1158/1538-7445.AM2017-2878