Colorectal cancer remains the second most common cause of cancer death in the United States, although as much as 70% of cases thought to be preventable through moderate dietary and lifestyle modifications (Anand 2008; Thompson 2011).
The colorectal cancer mortality rate has consistently declined in recent decades due largely to enhanced accuracy of early detection techniques, such as colonoscopy. However, the outlook for colon cancer patients rapidly diminishes if the cancer has metastasized to other organs or lymph nodes before detection.
If the cancer is detected while still localized in the colon, it is removed surgically and adjuvant techniques may be employed post-surgery to improve the chance for sustained disease-free survival. Treatment for advanced metastatic colon cancer usually encompasses multi-agent chemotherapy accompanied by palliative radiation.
Unfortunately, conventional standardized chemotherapy regimens may be ineffective for some patients due to genetic resistance against the drugs employed. Further, rarely do mainstream oncologists implement nutritional therapeutics or novel drug strategies to target genetic abnormalities associated with colon cancer growth, despite the fact that many peer-reviewed studies highlight the potential value of these agents.
Investigations have shown that several factors such as dietary habits, nutritional status, and inflammation influence the genetics involved in colon cancer development and progression, thus revealing multiple targets of interest in the prevention and management of colon cancer.
For example, a review of nine studies found that for every 10 ng/mL increase in serum vitamin D, the relative risk of colorectal cancer decreased 15% (Gandini 2011). Another landmark trial revealed that daily low dose aspirin reduced the risk of developing colon cancer by 24% and the risk of dying from the disease by 35% (Rothwell 2010).
In recent years, the introduction of advanced cancer analytical technology such as circulating tumor cell testing and chemosensitivity assays has improved outlook considerably by paving the way towards individually tailored treatments based upon the unique cellular characteristics of each patient's cancer.
In this protocol, you will learn about several unappreciated risk factors for colorectal cancer, and gain insight into several genetic and molecular mechanisms that drive the evolution from healthy cells to cancerous cells in the colon. You will also discover evidence-based methods for targeting these risk factors and carcinogenic mechanisms using natural compounds and novel drug strategies. Life Extension will also present resources and guidance for thoroughly analyzing the unique biological characteristics of your cancer cells, which is a critical step towards establishing an effective, personalized cancer treatment regimen.
About the Colon
The colon is the third-to-last section of the gastrointestinal tract in humans, followed by the rectum and anus. Food is mostly digested by the time it reaches the colon, so the role of this segment of the large bowel is to absorb water, some short chain fatty acids from plant fiber and undigested starch, sodium, and chloride, and compact waste to be eliminated during defecation. Moreover, colonic bacteria play a central role in metabolic detoxification by secreting chemicals that encourage excretion of toxins and pathogens. Beneficial bacteria in the colon (probiotics) also ferment dietary fiber and generate compounds, such as butyrate, which nourish cells in the colon wall and protect against carcinogenesis.
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 (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 (Benson 2007).
As mentioned in the introduction of this protocol, as much as seventy percent of colon cancers are thought to be preventable through diet and lifestyle modification (Anand 2008).
Factors such as diet, physical activity level, tobacco use, alcohol consumption and sleep patterns are associated with increased risk of colorectal cancers (Schernhammer 2003). 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 (NCI 2011).
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 (Bruce 2005). 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 (Larsson 2005).
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 (Yuhara, Steinmaus 2011).
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 (Thompson 2011).
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 (Pendyala 2011). 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 (Drew 2011).
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% (Boyle 2011).
InflammationPeople 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 (Mattar 2011). However, the inflammatory process is involved in the development of colorectal cancer growths even in those without Crohn's or ulcerative colitis (Rhodes 2002; Terzić 2010).
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 (Din 2010).
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 (Barresi 2008). 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 (Melstrom 2008). 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 (Yadav 2011; Bishnoi 2007).
For a complete discussion of the roles of COX-2 and 5-LOX in cancer development and progression, see the Cancer Treatment Critical Factors protocol.
More recently, NF-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 (Gupta 2011). 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 US or Europe (Aggarwal 2009).
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 (Smith 2010).
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% (Gandini 2011). 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 (Jenab 2010).
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 (Ng 2011).
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 (Freedman 2007). 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 (Kim 2010).
Pathology and Tumorogenesis
Colorectal cancers begin with epithelial cells that line the surface of the colon along finger-like projections called villi. The spaces between the villi are called crypts, and at the base of each crypt are immature stem cells that give rise to ever-renewing cells that migrate up the crypt and toward the tips of the villi. This normal cellular process is strictly governed by a balance of cellular renewal (normal proliferation) and cellular death (apoptosis), as well as elegantly choreographed expression of various genes along the path from immature stem cells to mature epithelial cells.
Early in the course of colon cancer development, however, the normal renewal of cells is disturbed. Cellular maturation (differentiation) is blocked and apoptosis is impaired leading to an accumulation of immature cells in the crypts. This is called an "aberrant crypt" and it is the first step in the carcinogenic process of colorectal cancers (Boman 2008; D'Errico 2008).These aberrant crypts almost always involve a genetic pathway that both embryos and colon cancer have in common, a pathway called Wnt (Abdul 2010). Many natural agents exert protective action through influencing this Wnt pathway, including components of black tea (Patel 2008a), green tea (Hao 2007) and turmeric (Mahmoud 2000).
Once the aberrant crypt forms, it may go on to become a polyp, which is a growth along the lining of the colon that can be seen during a colonoscopy exam. Polyps are benign, but they can progress to adenomas, which are considered precancerous. If further mutations occur, an adenoma can then progress to cancer over years or decades. This is the primary reason that screening colonoscopies are recommended, to remove the polyps or adenomas before they have a chance to become cancer.
Genetic Abnormalities in Colorectal Cancer
Several genes and/or genetic processes are frequently malfunctional in colon cancer cells, and therefore have become intriguing targets for treatment interventions. Some dietary compounds have been shown to influence these genes and may modulate colon cancer development and progression.
KRASKRAS is a gene that orchestrates cellular receptor sensitivity to a number of growth factors. When KRAS is activated, cellular proliferation is enhanced, while deactivated KRAS slows proliferation. In several types of cancer, including colorectal cancer, KRAS is mutated in such a way that causes it to be chronically activated, leading to unabated cellular proliferation. Mutations in KRAS are present in up to 40% of colorectal cancers (Thompson 2011).
While drugs that directly target KRAS are not yet available, the mutational status of this gene helps determine the likelihood that certain anticancer agents will be effective. For example, the anti-EGFR antibodies cetuximab and panitumumab may be ineffective if activating mutations in KRAS are present (Lin 2011).
Several natural compounds have been shown to target the KRAS pathway, including:
- Perillyl alcohol, a substance extracted from citrus fruits (Bland 2001; Asamoto 2002);
- Curcumin (Nautiyal 2011);
- Fish oil (Morales 2007);
- Tea polyphenols (Wark 2006).
Epidermal growth factor receptor (EGFR) is a protein expressed on the surface of epithelial cells that variably regulates a number of pathways involved in cellular growth and proliferation. The KRAS pathway is among those that EGFR effects.
Overexpression of EGFR is observed in approximately 65 – 70% of colon cancers, and is associated with an advanced disease stage (Thompson 2011).
Activation of EGFR stimulates KRAS-induced signal transduction leading to proliferation. However, in KRAS mutant (upregulation; overexpression) cancer cells, binding of EGFR is not necessary to activate KRAS. Therefore, medications sometimes used to treat colon cancer, called anti-EGFR antibodies, are only effective in patients not harboring a KRAS mutation (Bohanes 2011). For example, cetuximab is a monoclonal antibody against EGFR indicated for metastatic colorectal cancer in patients not carrying a KRAS mutation.
Natural compounds shown to modulate EGFR include:
- Genistein (an isoflavone from soy) (Yan 2010);
- Curcumin (Lee 2011);
- American ginseng (Dougherty 2011).
Note: Targeting EGFR directly may not be beneficial in a colorectal cancer patient overexpressing KRAS (constitutional activation). However, the aforementioned nutrients may also influence transcription downstream of EGFR and KRAS; thus they may be capable of inducing cell cycle arrest in KRAS mutant or wild type cancer cells. For example, curcumin was shown to act synergistically with dasatinib to reduce KRAS mutant colon cancer cell viability through alternative pathways (Nautiyal 2011); the other nutrients likely target additional pathways as well.
Microsatellite Instability (MSI) and Mismatch Repair Mutations
The human genome contains thousands of short, repeated base pair sequences called microsatellites, which vary in length from person to person, but are all the same length in an individual. DNA damage induced by factors such as oxidative stress and chemical carcinogens can cause dysfunction of genes responsible for ensuring that the microsatellites remain of consistent length; these genes are called mismatch repair genes. Mismatch repair gene mutations lead to microsatellite instability (MSI) – the lengthening or shortening of microsatellites. This causes dysfunction in the region of the genome containing the unstable microsatellites. If this occurs in a tumor suppressor region, the consequence can be uncontrolled cell growth, the hallmark of cancer.
Microsatellite instability is found in about 15% of colorectal cancers (Boland 2010).
Ironically, MSI (versus stable microsatellites) is associated with a better prognosis in colorectal cancer (Bohanes 2011), likely for the same reasons that it leads to cancer in the first place – the cells are unable to repair major DNA damage and thus more readily succumb to apoptosis.
- Tea polyphenols (Jin 2010; Dai 2008) have been shown to inhibit the proliferation of MSI colon cancer cells;
- Cells with disrupted MMR function are highly sensitive to the apoptotic effects of curcumin (Jiang 2010).
Screening for Colorectal Cancer
Colonoscopy is an endoscopic process using a lens that allows a physician to visualize the mucosa from the rectum to the start of the colon (ileo-cecal junction). Removal of adenomatous polyps during colonoscopy has been proven to lower the risk of colorectal cancer (Cummings 2011; Winawer 1993).
Screening colonoscopies are recommended beginning at age 50, but those with any risk factors and/or a family history should consider screening at an earlier age.
How a colonoscopy is performed and by whom may influence whether or not adenomas or cancers are detected. During a 15 month period, analysis of 7,882 colonoscopies performed by 12 experienced gastroenterologists found that the time it took to withdraw the colonoscope influenced detection rates. Gastroenterologists who took less than 6 minutes to withdraw the scope were much less likely to detect cancer than those who withdrew the scope more slowly (up to over 16 minutes.). Even advanced cancers were more likely to be missed when the scope was withdrawn more quickly (Barclay 2006).
The time of day the colonoscopy is performed may also influence its reliability. In a chart review of a total of 2,087 colonoscopies at Metro Health Medical Center in Cleveland, Ohio, those done in the afternoon had a significantly higher failure rate compared to those done in the morning (Sanaka, 2006). The "failure" of a colonoscopy means that the scope could not reach the start of the colon (the cecum). This incomplete look at the colon often necessitates repeating the scoping procedure or undergoing further imaging, such as a CT scan.
The rate of incomplete colonoscopies may be influenced by who performs the procedure. In a study designed specifically to look at factors that lead to incomplete colonoscopies, the elderly, females, and those that have had prior abdominal or pelvic surgeries are more likely to have an incomplete colonoscopic evaluation. In this same study, the researchers found that having the colonoscopy done in an office rather than hospital setting tripled the risk of new or missed colon cancer in men and doubled it in women (Shah 2007).
Computer Tomographic Colonoscopy (CTC) is sometimes referred to as a "virtual colonoscopy". It involves the use of CT imaging the colon. Preparation for CTC is much like a traditional colonoscopy with the use of laxatives to create an empty bowel. Carbon dioxide or air is infused through the rectum to create a smoother surface to assess. CTC's are useful for larger polyps but may not pick up smaller or flattened polyps as well as traditional colonoscopy. If any polyps or suspicious areas are seen on CTC, the patient must then undergo a colonoscopy to visually assess and/or remove the polyps.
CTC is limited in some extent relative to a traditional colonoscopy in that if a polyp is detected, it cannot be removed during the procedure. This is a disadvantage as the patient will then need to undergo a traditional colonoscopy following the CTC to remove the polyp. Another disadvantage of virtual colonoscopies is the high levels of radiation needed to perform the procedure.
Fecal Occult Blood Test (FOBT) Occult blood in the stool can be detected with a simple test and is recommended as routine screening for colorectal cancers. Long before blood can be seen by the naked eye, minute quantities may signify the presence of cancer. The association of a positive FOBT with actual colorectal cancer, however, is fairly low, only 10% (Manfredi 2008). This is because occult blood more often comes from benign conditions, such as minor hemmorhoids; a FOBT may even detect bleeding associated with the upper gastrointestinal tract.
The FOBT is about 70% sensitive to the detection of colorectal cancer, while a colonoscopy performed by an experienced gastroenterologist is roughly 95% sensitive (Rex 1997; Niv 1995).
Indirect Tests for Colon Cancer and Emerging Techniques
Colon Cancer Specific Antigens (CCSA's): A blood-based means of detecting colon cancer may be right around the corner. CCSA's are nuclear matrix proteins that are unique to colon cancer cells. When circulating, these CCSA's serve as a "fingerprint" indicating that either colon cancer or a premalignant adenoma is likely present (Leman 2008). Circulating levels of several of the CCSA's, including CCSA-2, CCSA-3 and CCSA-4 have all been independently shown to be both sensitive and specific to colon cancer or premalignant adenomas (Leman 2007; Walgenbach-Brunagel 2008). While this test is not commercially available yet, ongoing research is looking at optimizing combinations of the different CCSA's to predict the likelihood of colon cancer with great accuracy. In the future, this blood test may be used to gauge the urgency for colonoscopy screening.
Calprotectin in the stool has been used as a marker for IBD, and is a useful tool in determining the possibility of adenoma or colorectal cancer (Kronborg 2000; Roseth 1993). Fecal calprotectin is a product of granulocyte formation, a hallmark of chronic inflammation, and as such is not specific to the cancerous process but indicates that inflammation is present. In one study, of the patients referred for colonoscopy due to abdominal symptoms, elevated calprotectin was found in 85% of those with colorectal cancer, 81% of those with IBD and only 37% of those with normal findings (Meucci 2010).
Molecular Markers in the Stool: Since precancerous adenomas and colon cancer arise in the lining of the colon, the cells involved are shed with the stool on passing. With advances in technology and molecular biology, examining the stool for unique DNA changes that signify cancer is an area of interest.
The next generation of stool testing for colon cancer involves the stool DNA (sDNA) test, which was able to detect 64% of precancerous adenomas greater than 1 cm and 85% of colon cancers, and the fecal immunochemical test (FIT) (Ahlquist 2010). A patented stool DNA test called PreGen-Plus™ is approximately 65% sensitive to the detection of colorectal cancers (PreGen-Plus™ fact sheet 2011), but the high cost of this test may limit its utility for many consumers.
These non-invasive tests remain less sensitive than a colonoscopy, and have advantages and disadvantages that should be discussed with a healthcare provider (Cummings 2011).
Following diagnosis, oncologists and pathologists must analyze the extent to which the cancer has progressed and determine whether it has metastasized to other organs. This process, called "staging", is crucial in guiding treatment.
Cancer confined to the mucosa of the colon wall is classified as stage I and is easily removable by surgery in the great majority of cases. When the cancer has penetrated deeper into the muscle layers of the colon, or has just perforated the colon wall, it is classified as stage II. Stage II colon cancer also carries a fairly good prognosis. Stage III is defined by detection of cancer in nearby lymph nodes, tissues or organs. Stage IV colorectal cancer defines metastasis to one or more distant organs, such as the lungs.
The outlook diminishes as stages advance; surgery is usually no longer a curative option for cancer not contained within the colon or isolated to nearby tissue (colon cancer with isolated liver or lung metastasis can rarely be treated effectively with surgery). Five-year survival rates for stage I colon cancer are very good, at about 90%, while the median survival plummets to just six months in advanced stage IV cancer (Crea 2011).
A valuable innovation in cancer prognostic technology is circulating tumor cell testing. Circulating Tumor Cell testing involves the detection of cancer cells in the bloodstream. These circulating tumor cells are the "seeds" that break away from the primary site of cancer and spread to other parts of the body. Understanding circulating tumor cells is critically important since it is the spread of cancer to other parts of the body—and not the primary cancer—that is very often responsible for the death of a person with cancer. For a detailed discussion of circulating tumor cell testing, please refer to section three of the Cancer Treatment: Critical Factors protocol.