Project Funding Details

Background: Obesity is characterized by insulin resistance, inflammation, oxidative stress and proliferative stimuli, which can collectively impact on intestinal homeostasis, cancer risk and prognosis. Indeed, recent evidence, including our own preliminary data, suggests that the 'obese state' not only negatively impacts on intestinal tumor initiation, progression and metastasis, but also homeostasis and function, well before the onset of tumorigenesis. Considering the serious hazards posed by obesity on intestinal health, cancer development and metastatic disease, it is critical from a public health perspective to identify practical dietary strategies that can lessen this risk. Walnuts possess many beneficial, bioactive constituents that have been reported to have anti-cancer properties and could reasonably counteract many of the negative effects of obesity, thus representing a simple, yet effective strategy to mitigate obesity-related alterations on intestinal homeostasis. Objectives: The major goals of this proposal are to determine if a walnut-supplemented diet can mitigate the consequences of obesity on intestinal function, from preservation of 'normal' tissue and stem cell homeostasis, to a reduction in colon cancer incidence, progression and metastatic disease. Methods: To test our first objective, we will determine whether a walnut-supplemented diet can protect against obesity-related alterations in intestinal morphology, as well as intracellular signaling and oxidative damage. We will next use newly established technologies and tools to isolate Lgr5+ stem cells to perform gene expression profiling in these cells, as well as evaluate stem cell proliferation rates in vivo, using a lineage tracing approach. Our second goal will be to determine if a walnut-supplemented diet can attenuate the obesity-related increase in tumor incidence, multiplicity and burden, in a mouse model of intestinal cancer Apc1638/N+). Finally we will determine if a walnut-supplemented diet can reduce cancer progression, by injecting MC38 mouse colon cancer cells ectopically and monitoring tumor growth, and colon cancer liver metastasis by injecting MC38 colon cancer cells via the intrasplenic route into syngeneic C57BL/6 mice, and monitoring effects on liver metastasis by gross and histopathology. Potential Impact: Considering that most individuals who would be advised to supplement their diet with walnuts to lower their risk for colon cancer (and other diseases) are likely 'at risk' from overweight or obesity, it would be highly meaningful, from a public health perspective, to demonstrate a protective effect of a simple dietary strategy, such as walnuts, in this context. Furthermore, the feasibility of obtaining human specimens coupled with recent advances in isolating intestinal stem cells from human samples provide greater opportunities for discoveries here to be translated to future human intervention trials.

Over two-thirds of American adults are now overweight or obese, and it is well known that obesity can increase the risk for many ailments, including high blood pressure, high cholesterol, cardiovascular disease, stroke and diabetes. However, what is not as well known among the general public is that obesity also raises cancer risk, and once a cancer diagnosis is made, it leads to a worsened prognosis. For example, obesity increases the risk of developing colon cancer by 30-70% and the risk of dying from colon cancer by two-fold. Alarmingly, data from our lab and others suggests that many of the risks posed by obesity on developing colon cancer begin long before a diagnosis is made. Collectively, these results strongly warrant the identification of strategies that can help to minimize the risk of obesity on intestinal health and cancer risk. In theory, weight control would be the most obvious strategy to counteract the obesity epidemic, but in practice, this is not likely to succeed, because behavioral research has consistently shown that even if overweight individuals are successful at losing weight, they are often not able to maintain it. Thus, safe, practical and effective alternative strategies are needed, either to supplement a healthy lifestyle, or as an option for those otherwise vulnerable to the detrimental effects of obesity. One potentially simple, yet powerful approach is supplementing the diet with approximately a handful of walnuts every day. Accumulating evidence suggests that a modest serving of dietary walnuts are strongly associated with less risk for many diseases, including cancers. This may be due to the fact that whole walnuts are uniquely enriched in many bioactive compounds which can help to oppose many of the harmful 'side-effects' of obesity on cells and tissues. In order to determine whether this is the case, we will supplement the diet of mice either kept to a 'normal' weight with a healthy diet or made obese with a 'cafeteria' diet with walnuts, and determine whether walnuts are able to further improve several outcomes in healthy mice and/or prevent detrimental effects to occur in obese mice. We will specifically perform several state-of-the-art assays to evaluate not only intestinal health and function, but also effects on intestinal tumor development and metastasis. Considering that most individuals who might seek or be recommended to supplement their diet with healthy options such as walnuts to lower their risk for disease (including colon cancer) are likely 'at risk' from overweight or obesity, it would be highly meaningful, from a public health perspective, to demonstrate that walnuts are efficacious in this context. Furthermore, given that colon tissue biopsies are accessible for collection, discoveries from these rodent studies can be realistically used to support future human intervention trials with dietary walnuts to prove efficacy.