Primary prevention of colorectal cancer

Abstract

Colorectal cancer has been strongly associated with a Western lifestyle. In the past several decades, much has been learned about the dietary, lifestyle, and medication risk factors for this malignancy. Although there is controversy about the role of specific nutritional factors, consideration of dietary pattern as a whole appears useful for formulating recommendations. For example, several studies have shown that high intake of red and processed meats, highly refined grains and starches, and sugars is related to increased risk of colorectal cancer. Replacing these factors with poultry, fish, and plant sources as the primary source of protein; unsaturated fats as the primary source of fat; and unrefined grains, legumes and fruits as the primary source of carbohydrates is likely to lower risk of colorectal cancer. Although a role for supplements, including vitamin D, folate, and vitamin B6, remains uncertain, calcium supplementation is likely to be at least modestly beneficial. With respect to lifestyle, compelling evidence indicates that avoidance of smoking and heavy alcohol use, prevention of weight gain, and maintenance of a reasonable level of physical activity are associated with markedly lower risks of colorectal cancer. Medications such as aspirin and nonsteroidal anti-inflammatory drugs and postmenopausal hormones for women are associated with substantial reductions in colorectal cancer risk, though their utility is affected by associated risks. Taken together, modifications in diet and lifestyle should substantially reduce the risk of colorectal cancer and could complement screening in reducing colorectal cancer incidence.

Figure 1. Proposed insulin-related mechanisms that relate diet, obesity, and physical activity to colorectal cancer

Abdominal obesity, physical inactivity, and some aspects of a Western diet that stimulate insulin secretion could increase risk of colorectal cancer by causing repeated bouts of hyperinsulinemia. High levels of insulin might have direct effects on susceptible cells through insulin receptors or through IGF-1 receptors by decreasing IGF binding proteins thereby increasing free levels of IGF-1. Activation of insulin and IGF-1 receptors might lead to increased cell proliferation and reduced apoptosis, which could increase the risk tumorigenesis.

Figure 2. Proposed inflammatory mechanisms relating diet, lifestyle, and medication use to colorectal cancer

Dietary components (e.g. vitamin D and n-3 fatty acids), lifestyle factors (e.g. physical activity), and medications (e.g. aspirin, COX-2 inhibitors, NSAIDs), might have anticancer effects (red lines) whereas lifestyle factors such as obesity could promote cancer (black lines) through anti-inflammatory mechanisms that are largely mediated through inhibition of the COX-2 enzyme. COX-2 could be upregulated by inflammatory or oncogenic stimuli via inflammatory cytokines such as or interleukin-6 (IL-6) or others that induce nuclear factor κB (NF-κB). COX-2 converts membrane-associated arachidonic acid to prostaglandins, including PGH₂, PGD₂, PGF2_α, PGI₂ (prostacyclin), and thromboxane A2, as well as PGE₂. In turn, PGE₂ stimulates EP2, which upregulates transcriptional activity of β-catenin and activates the oncogene products phosphatidylinositol-3-kinase (PI3K) and the kinase AKT. PGE₂ also stimulates EP4, which triggers phosphorylation of the epidermal growth factor receptor (EGFR), thereby activating PI3K, AKT, and the oncogenic RAS–mitogen-activated protein kinase (MAPK) cascade. PGE₂ stimulation of PI3K signaling also activates the transcriptional activity of the peroxisome-proliferator–activated receptor δ (PPAR δ). These PGE₂-induced signaling pathways induce expression of a number of genes, including the angiogenic factor vascular endothelial growth factor (VEGF), the anti-apoptotic factor Bcl-2, and the proliferation-promoting factor cyclin D1. Many of the downstream targets of PGE₂ act in positive feedback loops to induce greater expression of COX-2 (green arrows). Aspirin and NSAIDs might also directly stimulate PPARs, and block phosphorylation of AKT. 15-prostaglandin dehydrogenase (15-PGDH) inhibits PGE₂ and thereby functions as a prostaglandin-degrading enzyme.– Upregulation of prostaglandin synthesis increases urinary 11 α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of PGE₂.

Figure 3. Proposed mechanism relating folate, alcohol, MTHFR genotype, and colorectal cancer

(THIS FIGURE IS BEING PREPARED BY ILLUSTRATOR) The TT genotype of MTHFR is associated with impaired function of the MTHFR enzyme in converting 5,10-methylene tetrahydrofolate (THF) into 5-methyl THF. For individuals with CC or CT genotypes, only modest associations are observed between folate, alcohol, and risk of colorectal neoplasia. However, individuals with the TT genotype might be particularly sensitive to the anti-cancer effects of high folate intake and low alcohol consumption. Specifically, with high stores of folate, the higher levels of 5,10-methyl THR might prevent imbalances of nucleotide pools during DNA synthesis (e.g. reduced uracil misincorporation) and a sufficient amount of 5,10-methylene THF is converted to 5-methyl THF for DNA methylation. In contrast, when the methyl content in the diet is low or depleted by alcohol consumption, individuals with TT genotypes might be less able to compensate for the impairment in MTHFR function; therefore, these individuals are less able to produce sufficient amounts of 5-methyl THF for DNA methylation. Impairment of DNA methylation processes results in dysregulation of gene expression.

Figure 4. Age-specific incidence of colon cancer per 100,000 person-years according to modifiable risk factors

Women were enrolled in the Nurses’ Health Study and were followed between 1980 and 2004. Women were assumed to have no postmenopausal hormone use, no aspirin use, average height, no family history of colorectal cancer, and have never been screened for colorectal cancer. 1) a "high-risk" participant (one who accrued 10 pack-years of smoking before age 30 years, had a consistently high relative body weight, had physical activity of 2 metabolic equivalent (MET)-hours/week, consumed 1 serving of red or processed meat per day, and had a folate intake of 150 µg/day); 2) a "moderate-risk" participant (one who was a nonsmoker, had an average body mass index, had physical activity of 13.5 MET-hours/week, did not consume red or processed meat, and had a folate intake of 300 µg/day); and 3) a "low-risk" participant (one who was a nonsmoker, had a consistently low relative body weight, had physical activity of 21 MET-hours/week, did not consume red or processed meat, and had a folate intake of 400 µg/day). Taken from Wei et al.

Figure 5. Age-specific incidence of colon cancer per 100,000 person-years according to modifiable risk factors and screening behavior

Women were enrolled in the Nurses’ Health Study and were followed between 1980 and 2004. Women were assumed to have no postmenopausal hormone use, no aspirin use, average height, no family history of colorectal cancer, and have never been screened for colorectal cancer. 1) a high-risk" participant (one who accrued 10 pack-years of smoking before age 30 years, had a consistently high relative body weight, had physical activity of 2 metabolicMET)-hours/week, consumed 1 serving of red or processed meat per day, was never screened for colon cancer, and had a folate intake of 150 µg/day); 2) a high-risk participant who was screened from age 50 years to age 70 years; 3) a "moderate-risk" participant (one who was a nonsmoker, had an average body mass index, had physical activity of 13.5 MET-hours/week, did not consume red or processed meat, was never screened, and had a folate intake of 300 µg/day); and 4) a “low-risk” participant (one who was a nonsmoker, had a consistently low relative body weight, had physical activity of 21 MET-hours/week, did not consume red or processed meat, was never screened, and had a folate intake of 400 µg/day). Taken from Wei et al.