1. Boman, Bruce M. MD, PhD, MSPH, FACP

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In a quest to understand how stem cells become overpopulated in cancer, my research team investigated the relationship between retinoic acid (RA) signaling and growth of colon cancer stem cells (CSCs). RA signaling was studied in normal and malignant colonic stem cells because aldehyde dehydrogenase (ALDH) is both a marker for stem cells in many tissues and a key enzyme in the RA pathway.

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Previous studies in my lab pinpointed ALDH as a biomarker for normal and malignant human colon stem cells and showed that ALDH tracks stem cell overpopulation during the formation of colon tumors. We found that retinoid receptors RXR and RAR are selectively expressed in ALDH+ stem cells indicating that RA signaling mainly occurs through ALDH+ stem cells, which provides a mechanism for therapeutically targeting CSCs.


Our report of this novel discovery, which could have a significant impact on the future of colorectal cancer (CRC) research and treatment, appeared in a recent issue of Oncotarget (2018;9:34658-34669). These findings suggest a new strategy for developing more effective stem cell-targeting therapies for the treatment of advanced CRC.


Studying Tissue Stem Cells

Conventional research over the last 50 years has been guided by the idea that tumors undergo a series of genetic mutations that lead to the unchecked growth of those tumors and their progression to metastatic cancer. Traditional therapies designed to kill tumor cells continue to fall far short of a cure for advanced CRC patients. Indeed, CRC is the second leading cause of cancer-related deaths in the U.S., equally affecting both men and women.


Our thinking has shifted to the insight that cancers originate in tissue stem cells through dysregulation of the stem cell self-renewal process, and that CSCs drive tumor growth. It follows that the optimal way to treat cancer (especially advanced cancer) is to eliminate CSCs. In our view, tumors develop when specific genes (e.g., the APC gene) become mutant because those are the genes that encode proteins that normally regulate stem cell renewal and stem cell population size.


We found that all-trans retinoic acid (ATRA), an RA ligand, down-regulates gene expression of the ALDH stem cell biomarker and reduces stem cell viability and renewal, and also abates growth of CRC cells. We also discovered that activation of RA signaling induces differentiation of colonic CSCs and reduces CSC overpopulation, which puts the brakes on the primary mechanism that drives CRC development.


Further study of the retinoid signaling pathway in normal and malignant colonic stem cells revealed that the anti-cancer effects of RA signaling in CRC occurs through decreased growth of ALDH+ colonic CSCs-the cells that carry the ALDH marker. RA, in parallel with increasing differentiation of CSCs, decreased CSC self-renewal and proliferation. Based on these findings, we believe that RA signaling provides a mechanism to selectively target colon CSCs and reduces self-renewal of those CSCs during CRC development.


Our findings suggest that treatment with retinoid drugs, which are derivatives of vitamin A, could provide a therapeutic strategy to selectively target CSCs and decrease the number of these highly resistant cancer cells. In our studies, we chose ATRA because it is one of the most commonly investigated and clinically tested RA derivatives.


Previous studies had shown that ATRA can reduce self-renewal in a number of other cancers. Indeed, ATRA has been used as a differentiation agent for in vitro studies and for clinical cancer therapy. For example, in breast cancer, it has been shown that ATRA caused cell differentiation in breast cancer cells and sensitized ALDH+ breast cancer cells to chemotherapeutics. Moreover, in the clinical treatment of acute promyelocytic leukemia, RA agents are highly efficacious and even curative.


BRUCE M. BOMAN, MD, PHD, MSPH, FACP, is a researcher at the Center for Translational Research of the Helen F. Graham Cancer Center & Research Institute at Christiana Care Health System, Newark, Del., as well as the University of Delaware, Newark.


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