As cancer death rates drop overall, doctors have noted a frightening anomaly: deaths from colorectal cancer in people under 55 appear to be creeping up. According to the American Cancer Society, deaths in this younger group increased by 1% between 2007 and 2016. The intestine and colon are hard-working organs. As you eat, your gut needs to constantly regenerate its lining to undo the damage done by digestive acids. To do this, the gut houses a population of stem cells that can replenish lining cells when needed. Scientists have found that colorectal cancers often originate from mutations in these stem cells. The most common colorectal cancer-linked mutation is in a gene called APC, which normally acts as a “tumor suppressor” gene because it controls how often cells divide. Mutations in the APC gene can remove that control and allow cells to divide rapidly and become cancerous. The researchers found that animals with an APC mutation, the most common genetic mutation found in humans with colorectal cancer, developed cancer faster when fed a high-fat diet.
Several researchs suggests that high-fat diets fuel colorectal cancer growth by upsetting the balance of bile acids in the intestine and triggering a hormonal signal that lets potentially cancerous cells thrive. The data suggest that lifestyle and genetics converge. The findings published in the journal Cell i 2019, could explain why colorectal cancer, which can take decades to develop, is being seen in younger people growing up at a time when higher-fat diets are common. The study was led by Professor Ronald Evans, director of the Gene Expression Laboratory, Howard Hughes Medical Institute investigator and holder of Salk’s March of Dimes Chair in Molecular and Developmental Biology. Over the last four decades, Evans and his colleagues have investigated the roles of bile acids. (30 types of bile acids float around in the gut to help digest food and absorb cholesterol, fats and fat-soluble nutrients). Among the lab’s discoveries was the revelation that bile acids send hormonal signals to intestinal stem cells through a protein called the Farnesoid X receptor (FXR).
For the new study, the researchers uncovered how high-fat diets affect that hormonal signaling by following a clue in a mouse model with an APC mutation. These mice develop early signs of colorectal cancer, so they monitored bile acid levels in the mice at the same time. They discovered that types of bile acids known to interact with FXR increased at the same time as cancer initiation–and that the presence of additional bile acids accelerated cancer progression. She saw a very dramatic increase in cancer growth correlated to bile acid, leading het to conclude that maintaining a balance of bile acids is key to reducing cancer growth. The researchers showed that feeding these mice a high-fat diet was like adding fuel to a fire: high-fat diets increased levels of two specific bile acids that dampen the activity of FXR. The gut wants to repair itself, and FXR keeps the process slow, steady and safe. When bile acids inhibit FXR, a group of stem cells starts growing rapidly and accumulating DNA damage.
The mice with APC mutations developed benign growths called adenomas. In humans, adenomas are common in the intestine and are routinely removed during colonoscopies. These growths normally take decades to turn into malignant adenocarcinomas. Yet the adenomas in these mice quickly turned cancerous when given high-fat diets. Scientists already knew that high-fat diets and bile acids were both risk factors for cancer, but they weren’t expecting to find they were both affecting FXR in intestinal stem cells. At last, the researchers had found a possible cellular mechanism to explain the rise in colorectal cancer deaths in younger people. Their theory is that as high-fat diets have become more common in the United States, more people with an APC mutation are accelerating their cancer growth through these diets. Next, the researchers decided to test a new cancer-fighting weapon. They used a molecule called FexD, developed to activate FXR in intestinal stem cells. FexD appeared to counteract the damage done by unbalanced bile acids in both mouse organ models and human colon cancer cell lines.
But why should gut cancer prefer a greater appearance in the young than in the elderly? The mechanism is probably linked to physiology, but also to daily choices. In the elderly, compared to the younger subject, the mechanisms of neoplastic transformation are more attenuated because old age does not allow rapid cell growth and tissue senescence represents a relative mode of protection. In the young, however, the potential for cell replication is greater and the dietary lifestyle is decidedly poorer for young people today than for those who are older. Moreover, the newest data from Dr. Evans’ lab indicate a deep correlation between this process and gut microbiota composition. His collegues found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenyl-alanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry.
Some biliary acids may stimulate cellular pathways involved in cell proliferation (protein kinase C or PKC). And a poor diet based with industrially-made foods is enriched in some fats (emulsifier diglycerides) that are natural activators of the same pathway. Along with potential carcinogenic substances in food and the diet-induced disbiosis, in the end the crircle gets closed on the genetic background for a potential onset of a gut neoplastic lesion.
Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Quinn RA et al. Nature 2020; 579(7797):123-129.
Fu T et al., Evans RM. Cell 2019; 176(5):1098-1112.
Romagnolo DF et al. Nutrients 2019 Jan 15; 11(1).
Cao L et al. Oncotarget. 2017; 8(38):63665-63679.
