Causes of and Risk Factors for Colon Cancer
Risk factors for colorectal cancer include age (90% is found in those over 50), personal history of polyps or adenomas, family history of colorectal cancer, and diagnosis of inflammatory bowel disease (IBD) (Crohn's or ulcerative colitis). Other risks include a diet high in fat or low in fruits and vegetables, physical inactivity, obesity, smoking and excessive alcohol consumption.5
As mentioned in the introduction of this protocol, as much as 70% of colon cancers are thought to be preventable through diet and lifestyle modification.1
Factors such as diet, physical activity level, tobacco use, alcohol consumption and sleep patterns are associated with increased risk of colorectal cancers.6 Obesity and physical inactivity are known to increase biomarkers of inflammatory processes, such as faecal calprotectin and serum C-reactive protein (CRP); elevated levels of inflammation are linked with higher rates of colorectal cancer. Greater vegetable and fiber intake has been associated with reduced levels of fecal calprotectin, a marker of intestinal inflammation.
A colon cancer treatment or prevention plan should start with foundational lifestyle measures that include physical activity and a diet rich in plant foods; patients should also strive to attain a healthy body weight.
Genetics and Family History
Genetic alterations, both inherited and non-inherited, are responsible for the carcinogenic process in colon cancer. About 75% of colorectal cancers are "sporadic," meaning that they arise in those without any family history of this disease, while the remaining 25% have an inherited predisposition that raises risk.7
Two familial disorders raise risk significantly, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC, or Lynch syndrome). These inherited disorders are responsible for 1‒2% and 3‒5% of all colorectal cancers, respectively.
Familial adenomatous polyposis syndrome causes hundreds to thousands of polyps to form before age 30 and often leads to colon cancer at a young age (average age 39 years old). Familial adenomatous polyposis arises from inherited mutations of the adenomatous polyposis coli (APC) gene, a gene mutation that is also present in 60‒80% of sporadic colon cancers.
Hereditary nonpolyposis colon cancer does not cause the multitude of polyps, but polyps are much more likely to become cancerous in those with this disorder. Those with hereditary nonpolyposis colon cancer have mutated mismatch repair genes (MMR genes), which fail to make necessary corrections to errors in DNA replication, allowing mistakes in the DNA to accumulate and colon cancer to ensue.
Metabolic Syndrome and Inactivity
Higher levels of insulin and glucose in the blood can increase the risk of developing colorectal cancers.8 An analysis of clinical data from 1966 through 2005 found that a diagnosis of diabetes raised the risk of colon cancer by more than 30% in both men and women.9
A recent study, which looked at much of the previous data on diabetes and risk of colon cancer, concluded that diabetes is an independent risk factor for developing colon cancer.10
The link between elevated insulin levels and colon cancer may be mediated though the insulin-like growth factor-1 receptor (IGF-1R). Insulin activates IGF-1R, which in turn functions to stimulate cellular growth and proliferation. Overexpression of IGF-1R has been observed in colon cancer cells, suggesting an increased sensitivity to the growth-promoting effects of insulin.2
Obesity is a risk factor for developing cancers in general, and studies show that reducing weight can reduce inflammation in the colon, thereby reducing risk of colorectal cancers.11 Adipose tissue (fat tissue) is not simply an inert storage system for excess calories—it actively produces many adipokines, or chemical messengers, that circulate throughout the body. One such adipokine, leptin, is linked specifically to the increased risk of developing colon cancer.12
Regular physical activity, which combats all the components of metabolic syndrome, is associated with a decreased risk for colorectal cancer as well. One study compared those who did not have a sedentary job with those that worked a sedentary job for 10 years or more; the risk of cancer arising in the left (distal) colon was doubled, and the risk of developing rectal cancer increased 44%.13
People with chronic inflammatory conditions of the bowel, such as Crohn's disease or ulcerative colitis (UC), have up to a six times greater risk of developing colon cancer than those without the conditions.14 However, the inflammatory process is involved in the development of colorectal cancer growths even in those without Crohn's or ulcerative colitis.15,16
Cyclooxygenase-2 (COX-2) is an enzyme that produces inflammatory end products by converting the omega-6 fatty acid arachidonic acid into prostaglandin E2, which promotes growth of cancerous cells; COX-2 is often overexpressed in colon cancer. Aspirin blocks COX-2 and has been shown to also lessen the development of colorectal cancers.17
5-Lipoxygenase (5-LOX), similarly to COX-2, metabolizes arachidonic acid into metabolites that drive development and progression of cancer. In colorectal cancer, 5-LOX expression was shown to correlate with the density of blood vessel growth within tumors.18 Moreover, 5-LOX is overexpressed in pre-cancerous polyps, and inhibition of 5-LOX caused a suppression of tumor growth in a murine colorectal cancer model.19 A compound extracted from Boswellia serrata, called 3-O-acetyl-11-keto-ß-boswellic acid (AKBA), is a powerful inhibitor of 5-LOX and may modulate the cellular properties of colorectal malignancies.20,21
For a complete discussion of the roles of COX-2 and 5-LOX in cancer development and progression, see the “Cancer Treatment: The Critical Factors” protocol.
More recently, nuclear factor-kappa B (NF-kB), a pro-inflammatory mediator that influences more than 500 genes involved in proliferation, angiogenesis, immune evasion and metastatic spread, has been the topic of intense research. Not surprisingly, NF-kB is a target for thwarting cancer's growth and many natural agents act on NF-kB to prevent its signaling. The most notable natural agent able to suppress NF-kB signal transmission is curcumin.22 The high intake of curcumin, and resultant inhibition of NF-kB, may be one reason that the incidence of colon cancer in India is so much lower than in the United States or Europe.23
Low Vitamin D Levels
More akin to a hormone than a vitamin, vitamin D broadly influences the genome by activating the vitamin D receptor in the cell nucleus. Activation of the vitamin D receptor is estimated to modulate as many as 2,000 genes, many of which are related to inflammation and cellular mutation—initial drivers in all cancers.24
As mentioned in the introduction of this protocol, a review of nine studies found that for every 10 ng/mL increase in serum vitamin D, the relative risk of colorectal cancer decreases 15%.3 These findings are consistent with the conclusion of a large, case-control study across 10 European countries, which also found that as vitamin D blood levels rose, the risk for colorectal cancer declined considerably. Compared with those in the lowest quintile (1/5th) (<10 ng/mL), those in the highest (>40 ng/ml) had a 40% lower risk of developing colorectal cancer.25
Individuals with colon cancer appear to have lower levels of vitamin D at the time of diagnosis as well. Serum vitamin D levels were insufficient (less than 29 ng/mL) in 82% of patients with stage IV colon cancer at the time of diagnosis.26
Low levels of vitamin D may adversely impact prognosis as well. One large study found an inverse association between serum 25-hydroxyvitamin D at the time of diagnosis and colon cancer mortality.27 Individuals with 25-hydroxyvitamin D levels over 32 ng/mL had a 72% reduction in mortality compared to those with blood levels less than 20 ng/mL.
Life Extension encourages the maintenance of serum 25-hydroxyvitamin D levels between 50–80 ng/mL for optimal health. This typically necessitates supplementation with 5,000–8,000 IU of vitamin D daily, but supplemental doses should always be determined by blood test results.
Low Folate and B-vitamin Intake
Homocysteine is an indirect marker for folate, B6 and B12 status. Homocysteine can be high when there is a deficiency in any of these B vitamins. Folate deficiency is associated with greater risk of developing colorectal cancers. In a large pooled analysis of data from 13 prospective studies including over 725,000 subjects, the highest quintile of folate intake was associated with a 15% reduced risk of colon cancer compared to the lowest quintile of intake.28