Study explores the effect of high-fat diet on intestinal stem cells and colorectal cancer
For years, epidemiological studies have pointed to obesity and a high-fat diet as significant risk factors for many types of cancer, including cancers in the colon and rectum. Now, a research team including Jatin Roper, MD, Director of the Center for Hereditary Gastrointestinal Cancer at Tufts Medical Center, believe they have discovered an important mechanism linking high-fat diet to intestinal cancers. The study results were published in the March 3 issue of Nature, one of the world’s most prestigious scientific journals. Dr. Roper was co-lead author of the paper, “High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.”
The researchers set out to test the effect of diet on intestinal stem cells, which have the capability to produce any other cell in the gut and can do so numerous times while maintaining their flexible state. Unfortunately, these abilities make stem cells excellent at generating tumors should they undergo cancerous mutations. To investigate a possible link between high-fat diet and intestinal stem cells and other cells in the intestine, the team fed healthy mice a diet made up of 60 percent fat for nine to 12 months.
Mice on the high-fat diet (HFD) gained 30 to 50 percent more body mass and developed more intestinal tumors than mice fed a normal diet. Dr. Roper and his colleagues also noticed that the HFD mice had many more intestinal stem cells, and that their stem cells were able to function without any input from neighboring niche cells, which regulate stem cell activity, telling them when to generate more stem cells or other specific gut cells.
When intestinal stem cells were grown ex vivo in a culture dish (away from niche cells), those from the HFD mice generated “mini-intestines” (miniature organs containing all cells found in the anatomy of real intestines) much more readily than cells from mice on the normal diet. This implies that high-fat diet alone may partially account for the higher number of intestinal tumors seen in obese patients by directly increasing divisions of stem cells—the suggested origin of colorectal and many other cancers.
In addition to observing this ability of the HFD stem cells to thrive without niche cells, the team also discovered a never-before-seen process. In mice on the high-fat diet, progenitor cells (stem cell offspring still able to produce a few other cell types) began to behave like stem cells—they lived longer and generated mini-intestines when grown outside the body. Primary investigator Omer Yilmaz, MD, PhD, of MIT, noted the significance of this transformation for cancer risk, as it increases the number of cells able to acquire mutations that give rise to tumors.
As for the mechanism behind this difference in stem and progenitor cell production and behavior, the researchers identified a nutrient-sensing pathway, PPAR-delta, a fatty acid sensor. This pathway responds to high levels of fat by activating a metabolic process that allows cells to use fat as an energy source instead of carbohydrates and sugars. The team found that in response to a high-fat diet, PPAR-delta also turns on a set of genes that affect stem cell identity, generating the effects seen in the study.
“These findings have potentially significant implications for research on a wide range of cancer types—our discovery may lead to other researchers’ searching for this effect in other systems of the body,” said Dr. Roper. “This result provides evidence of a direct connection between high-fat diet and cancer, at least in mice. We hope it will ultimately be an important discovery for human health, and we anticipate this research will contribute to the eventual development of cancer drugs to target tumors in obese patients. We will use our findings in future studies to seek a way to reverse this process.”
Dr. Roper received his medical degree from Boston University School of Medicine before completing his Internal Medicine residency at NYU Medical Center and his Gastroenterology and Hepatology fellowship at Tufts Medical Center. Dr. Roper and his team see patients with genetic predispositions for colon cancer and give recommendations on screening with the support of pathologists, colorectal surgeons, oncologists, genetic counselors and other cancer care team members.
Along with Dr. Roper, the Dana-Farber Cancer Institute’s Semir Beyaz and MIT post-doctoral fellow Miyeko Mana were lead authors of the study. Dr. Yilmaz and MIT’s David Sabatini, MD, PhD, were senior authors.
Dr. Roper’s research is supported by awards from the Department of Defense, the V Foundation and National Cancer Institute.