Editors' ChoiceCancer

Confetti illuminates the cryptic way calorie restriction protects from cancer

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Science Translational Medicine  05 Aug 2020:
Vol. 12, Issue 555, eabd4765
DOI: 10.1126/scitranslmed.abd4765

Abstract

Calorie restriction increases intestinal stem cell competition and decreases the retention of stem cells with mutations in mice.

Calorie restriction reduces the risk of a number of cancers, including colon cancer in preclinical models. Although the reduction in cancer incidence with calorie restriction has been well described, the mechanisms remain unclear. Bruens and colleagues aimed to shed light on these mechanisms.

The intestinal epithelium is comprised of crypts with stem cells residing at their bottom. The intestinal stem cells (ISCs) give rise to more differentiated cells that travel, like a conveyor belt, up the walls of the crypts to the tips of the villi from which they are shed. The external environment, including substances that may lead to cancer-causing DNA mutations, interacts with the ISCs. If an ISC acquires a DNA mutation, it will endow its offspring with the mutation, which could subsequently populate the villus. Previous studies in Drosophila have reported that calorie restriction enhances intestinal fitness by healthier cells outcompeting less healthy cells, but this phenomenon has not been described in mammals. Bruens and coauthors investigated whether calorie restriction in mice affected ISC competition.

The investigators found that calorie restriction led to the expansion of ISC numbers and crypt size. To understand whether the increase in the ISC population could affect tumor incidence, they used the tamoxifen-inducible confetti reporter. Upon treatment with low dose tamoxifen, one of four fluorescent proteins was expressed in one ISC from every 10 intestinal crypts. The progeny of the fluorescent ISC expressed the same fluorescent marker as the parent, so the lineage of a specific ISC could be traced. The authors used this technique as a proxy to model the fate of an ISC with a sporadic DNA mutation. They found that the fluorescent clones were smaller in size in the calorie-restricted animals than regular diet-fed animals. Additionally, the chance of the progeny of the fluorescent mutant cell occupying the intestinal villi was reduced in the calorie-restricted animals due to more ISC competitors.

A number of questions remain to be answered, such as whether cell competition is a hallmark of colon cancer development in humans, and indeed whether calorie restriction reduces cancer risk in humans, as it does in other mammalian models.

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