Project WCRF 2014/1181. World Cancer Research Funds (WCRF)

Early alterations of the intestinal stem cell niche underlie sporadic colon cancer driven by “Western-style” dietary factors

Summary

Although colon cancer is a prevalent disease at the population level, with sporadic cancer affecting ~6% of individuals at 50-60 years of age, it is rare at the cellular level: the frequency of 1-2 tumors per incident patient follows over 1012 cell divisions in the intestinal mucosa that take place over ~60 years. Thus, probability for tumor development is dependent on rare, possibly stochastic processes. Although several loci have been linked by GWA studies to colon cancer, mathematical modelling has raised doubts on whether such analyses can provide accurate and clinically useful evaluation of risk, in particular because of the strong impact of risk factors such ageing, diet, and inflammation. From this perspective, the current mouse models for intestinal cancer, mainly based on targeted mutations in the Apc tumor suppressor gene, fail to mimic the sporadic disease in the general population as far as the initial cellular alterations brought about by the above mentioned risk factors are concerned.

The lack of appropriate in vivo models represents a major obstacle towards the elucidation of the mechanisms through which specific environmental risk factors alter probability for sporadic colon cancer. However, the development of a “western-style diet” (NWD1) that, when fed to wild-type mice for long periods of time (12-18 months) causes colon tumors mimicking lag, incidence, frequency, and ratio of carcinoma to adenoma of human sporadic colon cancer, represents an important and novel experimental tool. The NWD1 diet is characterized by increased lipid content, and decreased vitamin D3, calcium, fiber and methyl-donor nutrients (folic acid and methionine), each component adjusted to nutrient-density levels associated with risk for colon cancer in diets consumed by western populations. Here, we plan to take advantage of these opportunities to model sporadic colon cancer in the laboratory mouse and combine them with sophisticated molecular biology tools which allow the study of the cellular alterations brought about by diet, i.e. possibly the main risk factor underlying colon cancer in the general population, in the colonic stem cell niche.

The main hypothesis that we plan to test is that colon cancer dietary risk factors primarily affect the composition of the intestinal stem cell niche before the rate-limiting genetic hit at the APC gene has occurred, by expanding the cell targets for tumor initiation and progression.

In order to test this hypothesis, we will model one of the main risk factor for colon cancer, namely diet, in otherwise wild type animals genetically modified only to allow the monitoring and lineage tracing of stem and ‘niche-supporting’ cells. In vivo and ex vivo functional analyses of these specific intestinal cell types will form the basis to elucidate the cellular and molecular alterations brought about by western style dietary factors which underlie colon cancer onset as it occurs in the general population.

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