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The promise of retinoic acid signaling
WILMINGTON, Del.—Colorectal cancer, which is the second leading cause of cancer-related deaths in the United States, could be coming under new fire soon, thanks to the discovery of a key signaling pathway. Researchers at the Helen F. Graham Cancer & Research Institute’s Center for Translational Cancer Research at Christiana Care Health System published work in Oncotarget regarding the impact of the retinoic acid (RA) signaling pathway on cancer stem cells and tumor growth.
“Our thinking has shifted to the insight that cancers originate in tissue stem cells through dysregulation or malfunction of the self-renewal process, and that cancer stem cells drive tumor growth. It follows that the optimal way to treat cancer, especially advanced cancer, is to eliminate cancer stem cells,” said Dr. Bruce Boman, senior research scientist at the Christiana Care Health System and leader of the Oncotarget study.
Boman tells DDNews that his lab has focused on the issue of cancer stem cells for nearly two decades, and says that in this work, “The real question is what is the difference between between a cancer stem cell and a normal stem cell? We need our normal stem cells for replacing our tissues, renewing our tissues for wound healing, so we really don't want to damage the normal stem cells in our body, but we really want to kill or eliminate the cancer stem cells in order to kill the cancer.”
Building off of previous exploration, in which Boman's lab had highlighted aldehyde dehydrogenase (ALDH) as a biomarker for normal and malignant colon stem cells, the scientists looked into ALDH further and found that as a part of the RA signaling pathway, it is functional in stem cells. Specifically, “We discovered that the retinoic acid or RA signaling pathway acts to induce differentiation of colon cancer stem cells and reduce cancer stem cell overpopulation, which puts the brakes on the primary mechanism that drives colon cancer development,” Boman explained.
The ability of retinoic acid signaling to inhibit colon cancer is a result of a decrease in ALDH-positive colon cancer stem cells, the team discovered. In addition, retinoic acid leads to increased differentiation of cancer stem cells, which in turn decreases their ability to self-renew and blocks cell proliferation, which is a strong advantage given cancer's unrestrained replication.
Based on the hypothesis that retinoid drugs could enable them to harness this approach and selectively target cancer stem cells, Boman and his colleagues tested all-trans retinoic acid (ATRA), a retinoic acid derivative. In studies of other cancer types, ATRA has proven capable of reducing the ability for self-renewal in cancer cells. In this work, it was found to down-regulate gene expression of the ALDH stem cell biomarker, reduce stem cell renewal and inhibit tumor growth. As noted in the Oncotarget paper, “Dysregulation of RA signaling in colonic [stem cells] likely contributes to overpopulation of ALDH+ [stem cells] and [colorectal cancer] growth.”
“Dr. Boman presents us with a broader view into the origins of colorectal cancer at the cellular and molecular level,” remarked Dr. Nicholas J. Petrelli, Bank of America endowed medical director of Christiana Care’s Helen F. Graham Cancer Center & Research Institute. “His work highlights the mission of the Center for Translational Cancer Research to hasten discoveries from bench to bedside, and draws us even closer on the path to targeted therapies that can improve survival and quality of life for patients with drug-resistant, advanced colorectal cancer.”