A study recently published in Nature seems to explain how obese mice, similar to obese humans, could be at an increased risk of colon cancer. Feeding overweight mice a high-fat diet resulted in the activation of a metabolism-regulating protein called PPAR-δ and a subsequent increase in the number of intestinal stem cells which could potentially give rise to tumors.
One of the lead researchers Ömer Yilmaz, a cancer biologist at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge stated that if similar physiological adaptations were seen in humans, the findings of various epidemiological studies could be explained.
“There has been an understanding that obesity causes an increase in cancer in various tissues. We intended to understand the mechanism behind this phenomenon”.
According to P Kay Lund who is a cell biologist at the University of North Carolina in Chapel Hill and the National Institutes of Health in Bethesda, Maryland, tissue samples from patients who have undergone colonoscopies could be analyzed to see whether PPAR-δ activity is enhanced, using it as an indicator for earlier preventive strategies.
Using Fat Mice To Understand Possible Association
Yilmaz, along with David Sabatini, who studies metabolism at MIT and the Whitehead Institute at Cambridge fed mice a high-fat (60 percent fat), high-calorie chow for approximately a year, after which the effects of the diet on the number and function of intestinal stem cells were tested.
The researchers observed that the diet not only made the mice want to eat more and become overweight, it also activated the PPAR-δ protein which stimulated the proliferation of intestinal stem cells. In another experiment, mice treated with a drug that activated the protein resulted in a similar cellular growth.
What’s To Blame – Food Or Weight Gain?
Presently, it has not been established whether the cellular changes are caused by weight gain and the accompanied metabolic changes, or due to the fatty food itself. The research team also assessed how intestinal stem cells that were grown in 3-D cultures known as organoids responded to fatty acids in the high-fat chow. The latter were also observed to activate PPAR-δ, indicating that the fatty acids might have a direct influence on the protein’s expression.
Nevertheless, and if this is the case, then could a similar mechanism exist in humans? Walter Willett, who studies Nutrition at the Harvard TH Chan School of Public Health in Boston, Massachusetts, cautions that increased body fat in humans is linked with an increase in the risk of cancer; however despite intensive research no significant link has been confirmed between a fatty diet and cancer.
“Data linking fat intake to the incidence of cancer is a mixed bag”, says Yilmaz. His team hopes to clarify the exact association between fatty acids and cancer risk by performing follow-up studies by feeding normal-weight mice the high-fat chow.
Key Question – Are The Results Reliable And Applicable To Humans?
A rather unsettling aspect is that many therapies that seem promising in mice are seldom effective in humans. More so, experimental treatments that are successful in a certain population of mice might not even work for other populations!
“We claim that mice are simpler, but the problem is deeper than that”, explains Caroline Zeiss, a Veterinary Neuropathologist at Yale University in New Haven, Connecticut. This suggests that rodent studies might be flawed from the beginning.
There are various reasons highlighting the possibility that studies performed on mice could be potentially confounding and non-generalizable to humans. These include the following:
- Researchers seldom report subtle environmental factors, such as the food given to their mice, their bedding and exposure to light. These conditions tend to vary significantly across labs and can affect the animals’ biology enormously.
- Dismissing mouse circadian rhythms could also create a bias in behavioral experiments – many humans would not perform optimally on social and cognitive tests if they’re made to do them in the middle of the night.
- Nutrition is another factor to consider – most researchers cannot even state where they obtain the feed for their mice. Certain foods contain estrogens and endocrine-disrupting chemicals which could affect results about cancer research and other diseases.
- The high-fat, high-sugar food administered during obesity-related studies often becomes rancid quickly, and the mice might stop eating it and lose weight without knowledge of the researcher.
- Food choices tend to alter a mouse’s gut microbiome, and a difference in gut bacteria also exists between different species of mice. This leads to differences in anxiety and behavioral tests.
- The competitive nature of science usually increases a researcher’s resistance to modifying how they select animals for their research design – old or ill animals may be considered simply to complete the research work.
Steps To Overcome Such Issues: Efficacy Of Mice Related Studies
Due to enormous data suggesting that mice-related studies might be riddled with limitations, the US National Institutes of Health (NIH) has taken certain steps to tackle some of these problems. These include:
- Requiring the animal trials of certain institutes to be replicated before a therapy can move into clinical trials. However the NIH currently has no plans to pursue this agency-wide.
- In 2014, the NIH urged researchers to include female animals in their studies, and began giving out supplementary grants to researchers who had issue with the cost.
Despite these potential steps, the NIH has not issued specific grants or supplements to investigate other confounding factors. Unless prospective steps are taken to limit the confounding variables listed above, it seems that research studies performed on mice will remain doubtful, especially the aspect of their results being generalized on humans.