Texas A&M AgriLife researchers develop dietary cancer prevention strategies related to stem cells
By: Paul Schattenberg, 210-859-5752, paschattenberg@ag.tamu.edu
Contact: Dr. Robert Chapkin, 979-845-0419, r-chapkin@tamu.edu
Eunjoo Kim, 979-845-0448, kim10023@tamu.edu
Robert Fuentes, 979-845-0448, nfuentes2@tamu.edu
COLLEGE STATION – Texas A&M AgriLife scientists have found a way to use novel combinations of dietary compounds to selectively delete damaged stem cells and suppress cancer-causing cell signaling.
“This research is necessitated by the fact that the number of cancer cases diagnosed annually by 2050 is likely to double as a result of current population aging,” explained Dr. Robert Chapkin, Texas A&M AgriLife Senior Faculty Fellow and Regents Professor in the department of nutrition and food science, College Station. “If we as a society hope to head off the coming storm, we must get more serious about cancer prevention. Therefore, stem cell targeted therapeutic strategies aiming to eradicate malignancies are necessary.”
Chapkin, also a Texas A&M AgriLife Research nutrition scientist, was recently recognized by the National Cancer Institute as an R35 Outstanding Investigator. His work and that of others in the Chapkin lab focuses on chronic disease prevention.
“We examine the effects of diet and gut microbe-derived bioactives on the inhibition or activation of genes involved in cancer development in humans,” he said.
Chapkin said work initiated by Eunjoo Kim, a graduate student in his lab, recently demonstrated long-chain omega-3 fatty acids found in fish oil have synergistic effects when combined with curcumin, which is found in turmeric, in dramatically reducing colon cancer risk.
“We applied this combination of bioactives in order to target leucine-rich repeat-containing G-protein coupled receptor 5, or Lgr5, stem cells, the cells-of-origin of colon cancer,” he explained. “Specifically, adult colonic Lgr5 stem cells preferentially damaged by carcinogenic activity are removed efficiently via programmed cell death.”
Chapkin said the ability to remove genetically damaged cells is important because residual DNA damaged Lgr5 stem cells generate defective progenitor cells and promote uncontrolled cell proliferation, which can be a factor in tumor development.
“Findings from current studies suggest that unique metabolites produced by microbes in the large intestine following the ingestion of curcumin, when combined with omega-3 fatty acids, are effective as colorectal cancer preventive agents,” he said. “Combination treatment of omega-3 fatty acids with curcumin results in a synergistic efficacy above and beyond omega-3 fatty acids or curcumin alone in deleting damaged Lgr5 stem cells at the tumor initiation stage.”
He said the same synergy is found at the pre-tumor stage of tumorigenesis in colon cancer.
“We demonstrated that omega-3 fatty acids combined with curcumin decreased levels of nuclear beta-catenin, which is a colon cancer marker protein,” he said. “In general, curcumin has a low bioavailability, but omega-3 fatty acids appear to maximize their chemo-protective effect.”
Researchers in his lab have made strides in explaining how the signaling nodes in Lgr5 stem cells are modulated by these dietary bioactives.
“We found that in the presence of carcinogen, omega-3 fatty acids combined with curcumin selectively act on Lgr5 stem cells by up-regulating the p53 signaling pathway in order to remove DNA damaged cells,” said Kim. “The p53 is a tumor-suppressor gene and functions mainly as a gatekeeper and caretaker for the cell. Gatekeepers regulate cellular functions involved in cell growth and cell death and caretaker genes control cellular process involved in stem cell repair of damaged genes and maintain genetic integrity.”
Chapkin also cited recent findings from Natividad Roberto Fuentes, a doctoral candidate in the lab, demonstrating that omega-3 fatty acids actually get incorporated into phospholipids that form the cell plasma membrane, while curcumin squeezes in between spaces within the membrane, leading to modulation of lipid and protein interactions.
“This suggests that their accumulation in the colon can disrupt the membrane structure and composition of epithelial stem cells, and helps suppress dysfunctional Wnt/beta-catenin signaling that can lead to colon cancer,” Chapkin said. “This is noteworthy, because Wnt/beta-catenin signaling controls intestinal stem cell fate and aberrantly activated Wnt signaling is found in colon cancer stem cells but not in normal cells.”
Chapkin said other Wnt repression strategies exist as therapeutic options for colon cancer, but diet-induced Wnt inhibition could represent a valuable alternative strategy for primary cancer prevention.
“Overall, these recent findings suggest that our therapeutic strategy for eliminating damaged stem cells and suppressing Wnt signaling using dietary and microbial bioactives could represent a novel target for the prevention of colon cancer and possibly other cancers,” Chapkin said.
