by Dr. Joseph Debé
Colorectal cancer is the second most common cause of cancer deaths, for both sexes, in the United States. The factors contributing to this condition are numerous. Some of the more important risk factors for colorectal cancer appear to be: excessive energy intake (eating too much), high fat-low fiber-high sugar diet, red meats (especially heavily browned meat from frying at high temperature), refined grains (bread, pasta, many cereals, potatoes, cakes, desserts), alcohol, omega 6 fatty acids and trans fatty acids (found in hydrogenated vegetable oils which are ubiquitous in convenience foods), iron, physical inactivity, obesity, constipation, gum disease, colonic inflammation, and family history of colorectal cancer or polyps.
On the other hand, many lifestyle factors protect against the development of colorectal cancer. These include (among others): vegetables, fruits, whole grains, dietary fiber, water, fish, omega 3 fatty acids, coffee (more so than tea), folic acid, multivitamins, vitamins B6, C, D, and E, selenium, calcium, physical activity, and aspirin.
As with all degenerative conditions, the risk to colorectal cancer results from a complex interplay of genes and environmental/lifestyle factors. For example, it appears that the risk associated with the consumption of red meat is modified to some degree by the activity of several detoxication enzymes. Individuals with a fast activity of the acetylating enzyme are at increased risk to colorectal cancer from consuming meat whereas the risk is much less for people with slow activity of this enzyme. This is because the acetylation of heterocyclic amines (which are formed in the cooking of meat) results in the formation of mutagenic (DNA-damaging) compounds. This is called bioactivation. After the body alters the structure of toxins in the first phase of detoxication, the resulting compounds are often more toxic and carcinogenic than the starting chemical! It is of critical importance that the activities of phase 2 detoxication enzymes keep up with the bioactivating phase 1 enzymes or risk to colon cancer increases. Phase 2 enzymes bind the partially transformed toxin from phase 1 to different chemicals manufactured within the body in order to make them water soluble and thus excretable. The activity of a phase 2 detoxication enzyme, glutathione S-transferase (GST), may also influence the carcinogenicity of meat. People with slow GST activity are at increased risk from meat consumption and at increased risk in general. GST plays a role in binding toxins (including carcinogens) to glutathione, which enables the body to excrete them. Studies have found people with colon cancer to have slower GST activity and several times greater sensitivity to chromosomal breakage upon exposure to toxins. Another study found that those colorectal cancer patients with greater GST activity survived longer. The activity of detoxication enzymes is partly under genetic control and can vary among individuals by a factor of fifty fold! Laboratory tests are available to assess the activity of GST and other important detoxication enzymes. The expression of the genes encoding for these enzymes can be modulated by other factors. For example, bile acids, compounds produced by the liver and secreted into the intestines to aid fat digestion, suppress GST activity. Elevated levels of colonic bile acids have been associated with colorectal cancer. GST activity is increased by: caloric restriction; glucosinolates which are compounds found in cruciferous vegetables (broccoli, Brussels sprouts, cabbage and cauliflower); allyl sulfides found in garlic, onions, leaks and chives; zinc; and D-limonene which is found in many plants, especially citrus peel, dill weed oil, and caraway oil. Most of these GST activating compounds are available in supplemental (pill) form. Oncoplex contains glucosinolates from broccoli sprouts; while Celapro is a supplement whose ingredients include D-limonene.
Red meat may also contribute to colon cancer by virtue of its high iron content. Both high dietary iron and high serum (blood) iron have been associated with increased risk to colon cancer. Iron and fat both decrease manganese superoxide dismutase (SOD) activity in the cells lining the colon. Manganese SOD is an antioxidant enzyme that protects mitochondria (the part of the cell where energy is produced from food and oxygen) from oxygen radical damage. The connection between healthy mitochondrial function and colon cancer will be described later. Manganese SOD has tumor suppressive activity and has been found lacking in most colon tumors. Supplementation with manganese can increase the activity of this enzyme. Iron is also a necessary nutrient for the growth of strains of intestinal bacteria that contribute to colon cancer. Iron may additionally contribute to colorectal cancer by spurring the production of highly destructive free radicals, which can convert procarcinogens to carcinogens and can also directly damage genetic material. This process is augmented by components of bile.
Bile contributes to colorectal cancer risk in other ways. Bile acids are mutagenic (cause genetic mutation), inhibit a phase 2 detoxication pathway called glucuronidation, and increase colon cell proliferation. Bile acids become even more carcinogenic after chemical modification by certain species of intestinal bacteria. These bile acids are referred to as secondary bile acids. A high-fat, low-fiber diet results in increased levels of secondary bile acids. Calcium apparently binds bile acids and inhibits them from stimulating colon cell proliferation. Calcium supplementation has been found to reverse premalignant changes within colon cells. The same effect was seen in a recent study in which individuals at high risk to colon cancer consumed low-fat dairy products supplying up to 1200 milligrams of calcium per day.
Although a high-fat diet is associated with colorectal cancer, it’s important to understand that all fats are not created equal. With regard to colorectal cancer, vegetable oils and animal fat are more of a concern than dairy fat, and fish oil is actually protective. Whereas red meat and most vegetable oils are high in omega 6 fatty acids, flaxseeds and some fish are rich in omega 3 fatty acids. (Incidentally, buffalo and ostrich are red meats with a lower, and qualitatively better, fatty acid composition than other red meats.) These two families of fatty acids are converted in the body into different types of eicosanoids, which are hormone-like compounds regulating diverse bodily functions. The enzyme which acts upon the fatty acids derived from vegetable oils and red meats to produce series 2 eicosanoids has been found to be dramatically increased in 85 to 90% of human colorectal adenocarcinomas (the most common type of colorectal cancer). Series 2 eicosanoids apparently contribute to the immortality of these cells and to their spreading from the colon. Alcohol, the blood sugar-regulating hormone insulin, and trans fatty acids all contribute to a relative excess of series 2 eicosanoids. Aspirin inhibits the enzyme responsible for production of the series 2 eicosanoids and has been found to induce apoptosis (programmed cell death) in colon cancer cells. Its regular use is associated with reduced incidence of colon cancer. Ask your doctor whether you should take a baby aspirin per day.
The fatty acids found in flaxseeds and cold-water fish can also lead to reduction in levels of series 2 eicosanoids. Fish oil fatty acids were found in an animal study to inhibit spread of cancer from the colon, apparently by reducing the ability of tumor cells to adhere to blood vessels. Other natural compounds also inhibit production of series 2 eicosanoids. These include bioflavanoids, ginger, curcumin, vitamin E, and zinc. All of these, as well as fish oil and flaxseed oil, are available in supplemental form. So is conjugated linoleic acid (CLA). CLA is unusual in that it is a fatty acid found in meat and dairy fat, yet it has anti-cancer properties. Animal studies have found it to be perhaps the most powerful tumor inhibitor of all the fatty acids. CLA has been found to reduce carcinogen activation as well as initiation and promotion of colon cancer. CLA has other beneficial effects, including enhancement of immune function, prevention of wasting states (excessive breakdown of healthy body tissue, often seen in advanced cancer), and improvement of glucose metabolism and insulin sensitivity.
Abnormal carbohydrate metabolism, with insulin insensitivity and subsequent high insulin levels, may contribute to colon cancer. Two large studies have found a significantly increased risk of colon cancer in people with diabetes mellitus. The high insulin levels present in type II diabetes (and in pre-diabetes and Syndrome X) probably acts as a growth factor, stimulating proliferation of colon cancer cells. The known colon cancer risk factors of: obesity, physical inactivity, and consumption of a high-fat, high-sugar, highly refined, low-fiber, omega 3 fatty acid-deficient, nutrient-poor typical American diet, all contribute to altered glucose and insulin metabolism. Restoring normal carbohydrate metabolism, which can be done through holistic methods, may protect against colon cancer.
Improving carbohydrate metabolism is just one of many ways dietary fiber may help prevent colon cancer. Fiber also leads to reduced production of secondary bile acids, adsorbs bile acids, increases fecal bulk thus diluting carcinogens, speeds transit time (the time it takes for food, and associated carcinogens, to pass through the gastrointestinal tract), tends to reduce caloric intake, and lowers pH by the production of short chain fatty acids. It is important to consume both soluble and insoluble fibers to gain all these benefits. Eating a variety of fruits, vegetables, legumes, whole grains, nuts and seeds will accomplish this goal.
A very important effect of fiber results from its metabolism by bacteria within the intestinal tract. The intestines are normally home to hundreds of trillions of bacteria comprised of some 400 species. Some of these produce more favorable metabolites for human health than do others. The "good" bacteria feed upon soluble fiber and produce compounds called short chain fatty acids, which have anti-tumor activity. Butyrate is the most important of the short chain fatty acids. The benefits of soluble fiber are minimized if there are not enough "good" bacteria to metabolize it. Antibiotics, poor eating habits, and stress are some of the common factors resulting in imbalanced intestinal flora, with inadequate numbers of friendly bacteria. Supplementing with proven quality strains of lactobacillus acidophilus and bifidobacteria is worth considering. The product I most recommend for this purpose is Ultra Flora Plus by a company called Metagenics. The number of acidophilus and bifidobacteria inhabiting the intestines can be assessed with some accuracy by laboratory testing. Getting back to butyrate, decreased concentrations have been found in colon cancer patients. In my experience of having my patients tested, low butyrate levels are a very common finding. Butyrate is the primary fuel source for colonic cells and is therefore required for their health. Animal studies have found butyrate to reduce the number of colon tumors formed. Butyrate appears to reverse premalignant colon cell changes induced by secondary bile acids. What this means in practical terms is a high fiber intake can reduce the risk associated with eating animal products.
Butyrate influences the tumor process in a number of ways, some of which involve up-regulation of expression of tumor-suppressor genes. For butyrate to induce these genes requires adequate mitochondrial function. The most common factors resulting in impaired mitochondrial function are nutrient deficiencies, toxicity (some antibiotics are toxic to mitochondria), and oxidative stress (free radical damage). Butyrate influences genetic structure, leading to DNA repair and thus preventing a cell from becoming malignant. By influencing genetic expression, butyrate inhibits tumor cell growth and induces apoptosis (self-destruction) within tumor cells. The activities of enzymes that inhibit the spread of colon cancer are also increased by butyrate.
The "bad" intestinal bacteria generate free radicals and activate procarcinogens to carcinogens, thus contributing to colon cancer. In fact, after reviewing 270 studies, researchers at the Environmental Protection Agency’s Genetic Toxicology Research Division concluded that most cancer-causing agents require bioactivation by intestinal bacteria before exerting carcinogenic activity! There are a number of bacterial enzymes that increase risk to colorectal cancer. Two of these enzymes are beta-glucuronidase and mucinase. Beta-glucuronidase breaks the bond between toxins and glucuronic acid, which like glutathione, is a compound the body produces and attaches to toxins to make them water soluble and thus able to be excreted. The effect of beta-glucuronidase is therefore liberation of bound toxins, allowing them to once more damage the body before being detoxified again. Mucinase is a bacterial enzyme that contributes to the breakdown of mucins, protective compounds coating the gastrointestinal tract. Mucinase thus increases the exposure of colon cells to carcinogens. The bacteria producing these enzymes tend to be those which feed upon meat. When you eat, so do your intestinal bacteria! The bacteria over-proliferate when an excess of undigested food makes it their way (into the colon). Therefore, assuring proper digestion and not over-eating are important considerations. Constipation also contributes to increased activity of these bacterial enzymes. The activity of these enzymes is decreased by: vegetarian diet; whole grains; skim milk; the soluble fibers, apple pectin and inulin; the friendly bacteria, acidophilus and bifidobacteria; calcium D-glucarate; the herbs, silymarin and lemon grass; and the spices cumin and black pepper. In an animal study, bifidobacteria and inulin have also been found to decrease levels of ammonia, which is a tumor promoter produced by bacterial degradation of protein and urea. The same study found reduced premalignant changes and apparent inhibition of tumor promotion. Inulin and bifidobacteria were both effective alone, but more so when combined. Another animal study in which a carcinogen was administered, found lemon grass to reduce DNA damage, reduce precancerous cell changes, and inhibit tumor initiation and promotion. Apple pectin has also been found to lower concentrations of series 2 eicosanoids and reduce tumor incidence.
Plant-based diets protect against colon cancer for a multitude of other reasons. High folic acid content is one very important reason. Insufficient levels of the B vitamin, folic acid, result in reduced activity of a process called methylation. Impaired methylation of DNA allows for the expression of oncogenes (tumor genes). Oncogenes and tumor suppressor genes appear to play major roles in colorectal cancer. Oncogenes are present in everyone and are, at least in some instances, genes that play roles in embryonic development. Afterward, these genes are normally inactivated and stay that way. However, a number of factors can result in reactivation of these genes. When oncogenes are expressed later in life, they do not contribute to normal physiology but rather initiate malignancy. Inadequate methylation of oncogenes is one way they become activated again. The amino acid (protein component) methionine is also necessary for methylation, while alcohol interferes with the process. One study found the combination of more than two alcoholic drinks daily along with low folic acid and methionine intake increased the risk to colon cancer by 330%. The risk for cancer of the last portion of the colon specifically, rose to 744%.
Phytonutrients are chemical compounds found in plants, which are not essential nutrients like vitamins or minerals, but are of importance to human health nonetheless. There are many ways phytonutrients protect against cancer. These include: enhancement of detoxication; inhibition of angiogenesis, which is the growth of blood vessel networks needed to foster growth and spread of the tumor; and anti-protease activity (proteases are enzymes used by tumors to destroy surrounding healthy tissue, allowing the tumor to spread). Phytic acid, found in most seeds and cereal grains, is one example of a phytonutrient with anti-tumor activity. Perhaps part of its effect is due to its ability to bind iron. Animal studies have found phytic acid to reduce precancerous changes in the colon, an effect which was enhanced by the addition of the potent antioxidant, green tea.
Plant foods are rich in antioxidants – compounds that neutralize the carcinogenic action of free radicals. Antioxidants contribute to favorable genetic expression. They also optimize the activity of tumor suppressor proteins, which repair genetic mutations and initiate programmed cell death when mutations are too extensive for repair. Reduced glutathione is the most important antioxidant within cells and is the compound most responsible for assuring proper functioning of these vital processes. A patented supplemental form of reduced glutathione called Recancostat has produced remarkable results in a small study of eight patients with metastatic colorectal cancer whom failed to respond to standard treatment. Seven of the eight patients improved, exceeded life expectancy, and at least two are in full remission.
Another antioxidant of particular importance in the prevention of colon cancer is the mineral selenium, which is necessary for the function of the body’s antioxidant enzyme, glutathione peroxidase. In addition to antioxidant effects, selenium inhibits tumor cell growth by reducing DNA synthesis, neutralizes the toxicity of mercury, and also increases immune function. Animal studies have found selenium supplementation to prevent tumor formation after exposure to a known colon carcinogen. This effect was enhanced by a low fat diet. A human trial of selenium supplementation found a significant reduction in colon cancer rates. Tests are available to measure levels of selenium, reduced glutathione, other antioxidants, and free radical activity.
Free radicals are also involved in another process contributing to cancer – inflammation. Parasites and toxic bacteria are common causes of colonic inflammation. The dietary factors that promote colon cancer are the same that promote inflammation. Inflammation plays a role in metastasis as well. Inflammation can be identified on colonoscopy. Elevations of fecal lysozyme also are a sign of inflammation. Lysozyme is a compound produced by the body, which destroys the cell wall of certain types of bacteria. Lysozyme is elevated in cases of colonic inflammation and colon cancer. Secretory IgA (SIgA) also gives some indication of the immune status of the colon. SIgA is the main antibody protecting the gastrointestinal tract from parasites, bacteria, viruses, fungi, food antigens, and toxins. Suppressed levels of SIgA lead to weakened immunity. Elevated levels of SIgA signify immune activation/inflammation. Lysozyme and SIgA can be measured from a stool specimen. Abnormal levels should prompt investigation as to the cause and lead to appropriate therapy.
The status of the immune system is very important in reducing risk to colon cancer. Natural Killer (NK) cells are immune system cells of particular importance in destroying cancer cells. Such things as nutrient deficiencies, toxicity, and stress (high cortisol to DHEA ratios) suppress NK cell activity. These factors can all be assessed with laboratory testing. NK cell activity is increased by, among other things, exercise, selenium, vitamin C, and various supplemental plant polysaccharides (starches) such as arabinogalactans. Arabinogalactans have the added benefits of increasing short chain fatty acids and inhibiting spread of tumor cells to the liver by blocking binding sites they use for attachment.
A thorough investigation of your overall physiology and lifestyle habits can identify which areas need attention in your case to lower risk to colorectal cancer. In my opinion, the Comprehensive Digestive Stool Analysis is a test everyone should take periodically. It gives an indication of the tumor-promoting potential of your colonic environment by measuring levels of "good" and "bad" bacteria, activity of the bacterial enzyme beta-glucuronidase, secretory IgA, short chain fatty acid distribution, butyrate, Ph and more.