JNI Oncology Lectures
Speaker: Leonard Augenlicht (Albert Einstein College of Medicine, Bronx, NY USA)
Subject: Nutrient genetic interactions in sporadic intestinal cancer
Location: Erasmus MC Rotterdam
Date: Wednesday, 04.05.2016, 11:00-12:00
Author: Edgar Schönfeld
In his talk, Leonard Augenlicht elucidated the influence of our diet on the occurrence of colon cancer.
Worldwide, colon cancer is the 3rd most common cancer in men and the 2nd most common cancer in women. However, it is much more prevalent in western and developed countries than in the rest of the world. The highest estimated incident rate is found for Australia (>30 per 100,000), while Western Africa exhibits the lowest incident rate worldwide (ca 4 per 100,000) . Twin studies, as well as studies on migrating populations, have confirmed that environmental factors contribute far more to the occurrence of colorectal cancer than genetic factors. Prof. Augenlicht estimated that we could reduce the incidence of colorectal cancer by 90% if we are able to determine the environmental factors that contribute to this malignancy.
In the vast majority of cases, colorectal cancer is initiated by a mutation in the tumor suppressor gene APC. Only 1-2% of all cases occur through an inherited APC mutation (1 wild type and 1 mutated copy of the gene) while sporadic colorectal cancer accounts for circa 90% of all cases (patients are born with 2 wild-type APC alleles). In the latter case, the first allele is hit on average at the age of 40 years, while the second hit usually occurs at the age of 50-60. The central question is: How do environmental factors increase the probability of such a hit?
To examine the impact of our diet, Augenlicht and colleagues fed mice on the “New Western-style Diet” (NWD). The nutrient composition is inspired by the average USA human diet, which is high in fat and low in fibers, calcium, and vitamin D . They observed that 20% of the mice developed 1-2 tumors at circa 2/3 of their lifetime. That makes it actually the only mouse model of truly sporadic colorectal cancer. In fact, the NWD amplifies tumor development in all mouse genetic models. The diet does not seem to cause mutations directly, but to rather influence gene regulation: In the inner layer of the gastrointestinal tract (mucosa), the diet perturbs cell maturation, alters the expression of lineage-specific cell markers and elevates Wnt signaling in the villi and crypts, just to name some important examples. Intriguingly, all these effects can be reversed by a “rescue diet”, having raised levels of calcium and vitamin D. In addition, the stem cells in the intestinal crypts (Lgr5+ cells) show a high expression of the vitamin D receptor. Those cells, in turn, are known to initiate colorectal tumor formation (an APC mutation in a Lgr5+ cell will result in a tumor). This led Augenlicht to take a closer look at Lgr5+ cells in mice fed with the NWD, using a technique called lineage tracing (see my last post, or this review on lineage tracing: http://dx.doi.org/10.1016/j.cell.2012.01.002). The constant renewal of the inner layer of the gastrointestinal tract is fueled by Lgr5+ stem cells which reside at the bottom of the intestinal crypts. These cells constantly produce new cells, which subsequently move towards the top of the crypt. However, this process is highly compromised in mice fed on western diet compared to mice fed on a control diet. Inspired by these findings, the researchers fed mice a normal diet, in which only vitamin D levels were decreased. Again, compromised cell migration was observed. Last but not least they used tamoxifen to knock out vitamin D receptors in Lgr5+ cells only, observing the exact same effect (Fig.2).
In conclusion, vitamin D is a key factor in determining Lgr5+ cell function. This finding may also explain why animals fed on western diets often loose hair, as Lgr5+ stem cells also reside in the hair follicles. Prof. Augenlicht’s research on the impact of the western diet is ongoing. Recent findings suggest that the western diet actuates a metabolic switch, causing cells in the mucosa to favor glycolysis over the citric acid cycle for generating energy.
With more research to come in the following years, I am curious to see how these scientific findings will influence our culinary preferences.
How should we adjust our diet in order to minimize the risk of colorectal cancer? According to the US National Cancer Institute “There is no reliable evidence that a diet started in adulthood that is low in fat and meat and high in fiber, fruits, and vegetables reduces the risk of CRC by a clinically important degree” (“PDQ (Physician Data Query) – NCI’s comprehensive source of cancer information”, Status as of 11.02.2016) . The same report states “The evidence is inadequate to determine whether calcium supplementation reduces the risk of CRC”. I conclude that we have to wait until we know more. Until then, try to avoid the usual risk factors such as smoking, excessive alcohol use, and obesity.
1: GLOBOCAN 2012: estimated cancer incidence mortality and prevalence worldwide in 2012, Factsheet Colorectal Cancer, World Health Organization (http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx?cancer=colorectal)
2: Newmark HL, Yang K, Kurihara N, Fan K, Augenlicht LH, Lipkin M. Western-style
diet-induced colonic tumors and their modulation by calcium and vitamin D in
C57Bl/6 mice: a preclinical model for human sporadic colon cancer.
Carcinogenesis. 2009 Jan;30(1):88-92.
3: Peregrina K, Houston M, Daroqui C, Dhima E, Sellers RS, Augenlicht LH. Vitamin
D is a determinant of mouse intestinal Lgr5 stem cell functions. Carcinogenesis.
4: “Colorectal Cancer Prevention–Health Professional Version (PDQ®)”(Status as of 11.02.2016) http://www.cancer.gov/types/colorectal/hp/colorectal-prevention-pdq#section/all