Abstract
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.
See also:
- Official Web Site: The Di Bella Method;
- Solution of retinoids in vitamin E in the Di Bella Method biological multitherapy;
- Somatostatin in oncology, the overlooked evidences - In vitro, review and in vivo publications;
- The Di Bella Method (A Fixed Part - Cyclophosphamide and/or Hydroxyurea tablets, one or two per day);
- Complete objective response to biological therapy of plurifocal breast carcinoma;
- Neuroblastoma: Complete objective response to biological treatment;
- Oesophageal squamocellular carcinoma: a complete and objective response.
The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDHplus colon cancer stem cells and increased differentiation of stem cells - Supplementary Files