Introduction:

Colorectal cancer, also known as colon cancer, is a cancer that starts in the colon or large bowel and could extend to the rectum, the end of the large intestine. Blood in stool, change in the bowel movements, weight loss, feeling weak and tired are the common signs and symptoms. Although genetic or family history of colon cancer and colon polyps, is currently considered the principal risk factor, only a small fraction of the population, 5-25% only have such a history. But constipation specially in old ages when the large bowel like many other parts of the body is more vulnerable and weak, and mostly occurs as a result of diet high in meat and low in fiber increases the risk of colorectal cancer. Other diseases of the small and large bowels such as inflammatory bowel diseases, including Crohn’s disease and Ulcerative colitis, and also polyps of the large bowel could increase the risk of colorectal cancer. In fact the cancer often typically starts as a polyp and a benign tumor that over time grows and spreads and becomes a killer cancer. Globally, colorectal cancer is the third most common type of cancer making up about 10% of all cases, with about 1.5 million new cases and 700,000 deaths per year, and the second leading cause of death from cancer in the the developed or Western societies. Colorectal cancer is one of the few diseases that is more common in developed countries than the developing or under-developed lands that carry most of the human’s diseases due to infections, poor hygiene, poverty and insufficient medical care. (1-3)

The Normal & healthy Colon:

The normal function of the colon is fermentation of undigested food remnants such as starch and protein in order to extract energy from otherwise indigestible carbohydrates, production of vitamins, to absorb water and electrolytes and to transport waste products (feces) to the rectum for excretion/defecation. Food remnants, intestinal secretions, digestive juices and exfolated intestinal cells are metabolised by the bacteria (microbiome) in the colon. (4) In the bottom of each colonic crypt, 4-6 stem cells give rise to the enormous amount of colonocytes and host the potential of accumulating genetic and epigenetic changes. (5) As a result of the ongoing and rapid proliferation, the colonocytes move from the lower parts of the crypts up towards the colonic lumen at a speed of approximately 1 cell position per hour. When colonocytes reach the luminal surface they are exfoliated. Thus, a crypt is fully renewed in 2-8 d. The total proliferation rate is 3-10 billion colonocytes per day. This makes the colonic mucosa the organ with the highest proliferation rate of all organs in mammals. The rapid replication of cells require a readily available supply of nutrients for tissue synthesis and the process is very responsive to dietary changes. (6)

The colon hosts a major part of the human microbiome consisting of approximately 0.5-1 kilo of bacteria of thousands of different and mostly anaerobic strains. The number of bacteria in the microbiome is approximately 10 times the number of cells in the entire body and has an overwhelming impact on human health. (7-8) Later in life the microbiome is typically characterized by a reduced biodiversity with an increased abundance of opportunistic facultative anaerobes, and a decreased abundance of species with anti-inflammatory properties. The age-related proliferation of opportunistic bacteria could contribute to an environment predisposing for diseases known to increase with age, such as colorectal cancer. Moreover, changes in the number, diversity and stability of commensal bacteria (dysbiosis), especially in the Clostridia group, also can alter normal physiological processes and lead to diseases including cancer. (9-10) Fermentation of dietary fibres results in the production of short chain fatty acids with the primary being butyrate, acetate, and propionate. Under optimal conditions, these fatty acids are the main and preferred source of energy for colonocytes. Taken together, a diet high in fermentable fibre and low in total energy and protein is considered a low-risk diet in relation to Colorectal cancer. A low-fat diet and energy restriction also lowers the abundance of opportunistic pro-inflammatory pathogens, which could represent Colorectal cancer bacterial drivers. (11)

The Abnormal & unhealthy Colon:

Undigested remnants of dietary protein and other nitrogenous compounds such as shed epithelial cells undergo bacterial degradation/fermentation producing ammonia, phenols and hydrogen sulfide. Furthermore, nitrate and nitrite are found in processed meat, that all these chemical compounds in the colon has been shown to cause inflammation and mucosal damage. Free ammonia is considered the most toxic of these substances. It is easily absorbed by colonocytes and induces inflammation, increases proliferation rate and raises the intraluminal pH, which again affects colonocyte function and oxygen levels in the mucosa. (12) Secondary bile acids such as deoxycholic acid and lithocholic acid have also been linked to increased Colorectal cancer risk. These bile acids are formed after enzymatic deconjugation and dehydroxylation of primary bile acids in the large bowel by anaerobic bacteria, and doubled in response to a high animal fat diet. (13-4)

 Arachidonic acid (AA) is an essential fatty acid and a major constituent of biomembranes. It is released from cellular membranes by enzymatic activity of phospholipase A2 and converted into various lipid mediators that exert many physiological actions. (15) The AA metabolism is one of the major inflammatory pathways triggered by direct contact between the bowel wall and fecal water irritants, pro-inflammatory microorganisms and luminal carcinogens. The most important enzymes converting AA into pro-inflammatory cytokines are the cyclooxygenase enzymes (COX) and especially the inducible cyclooxygenase-2 enzyme COX2. The major end-product of AA is the prostaglandin E2 (PGE2), which induces proliferation, suppresses the immune system, and stimulates angiogenesis by inducing production of vascular endothelial growth factor and fibroblast growth factor. Lipid mediators derived from AA metabolism, particularly PGE2, are associated with various diseases including Colorectal cancer, mainly based on the fact that COX inhibitors are effective chemopreventives. (16-7) Aspirin, which is the only non-selective and irreversible COX-inhibitor is effective in Colorectal cancer prevention and may reduce lifetime risk of CRC by 25%-50%. Apart from inflammation, the COX2 activity is up-regulated during Colorectal cancer carcinogenesis from epigenetic and genetic events in neoplastic cells. Mutation of the important “gatekeeper” gene APC (see later) results in increased COX2 activity and human Colorectal cancer cells generally have increased COX activity and PGE2 levels. (18-9)

The Risk Factors:

As it was mentioned in the introduction, the genetic risk of colorectal cancer, like many other cancers posted on this site, is very narrow and the majority are caused by the epigenetic or environmental factors. These factors in general for most cancers are infections and inflammations, but depending on the type and involved organ include specific factors as well. Since Colon as detailed above is a site of food digestion and part of alimentary system, so the diet, motility of the bowel and aging are the specific factors that affect the health of colon.

Infections & Inflammations:

As explained above, colon or large bowel is the site of more microbiata than the entire body, for fermentation of undigested food remnants. Aging is associated with reduction in the biodiversity of these micorbiata and increased of opportunistic facultative anaerobes, decreased abundance of species with anti-inflammatory properties, and conversely increased inflammation and infections. (9-10) That is one reason that the colorectal cancer is more frequent and a rule in the old age, in addition to the other factors such as decrease in physical activities, bowel motility and constipation that occur by aging and all in turn trigger inflammation and infection of the large bowel.  

 There is strong evidence of the link between inflammation and carcinogenesis of colon, through the increase of the cytokines, and other immune mediators as well as disturbance of the host/microbiome mutualism, including initiation, promotion, progression and metastasis. Indeed, carcinogenesis may be initiated by bacteria with pro-carcinogenic features, so called bacterial drivers, but other unknown pathogens like bovine viruses may also be involved. (20-2) People with inflammatory bowel disease account for less than 2% of colon cancer cases yearly. In those with Crohn’s disease 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years. In those with ulcerative colitis approximately 16% develop cancer of the colon over 30 years. The Crohn’s and ulcerative colitis, two autoimmune and inflammatory conditions of the small and large bowels are both suspected to have been induced by viral infection, and that such chronic infection of the mucosa may lead to ulceration and occasionally cancer. Duodenal ulcer disease and Crohn’s disease may on the other hand, be due to activation of latent viral infection of the corresponding neural ganglions, with subsequent migration of virus along the nerves to the gut wall. Correspondingly, non-ulcer dyspepsia as well as irritable colon may reflect viral infection of afferent nerve function leading to pain and discomfort. (23-4)

There have also been reports of the link between some bacterial infections and the colorectal cancer, even as remote as bovine carditis, brain abscess, or streptococcal bacteremia. (25-7) The increased risk of rectal and anal cancers in homosexual of about 47.1% in comparison to 28.6% in heterosexual men, and 28.3% in women with a history of genital warts, compared with only 1-2 % of controls have been linked to HIV and sexual transmitted diseases. Also gonorrhea in heterosexual men increases such cancers risk to about 17%, and seropositivity with herpes simplex type to 4%, infection with Chlamydiain women up to > 2%. (28) The list of infections associated with colorectal cancers are extensive and are of unusual types, e.g. endocarditis, meningitis, nontraumatic gas gangrene, empyema, hepatic abscesses, retroperitoneal abscess, clostridial sepsis, and colovesical fistulae with urosepsis, non traumatic crepitant cellulitis, suppurative thyroiditis, pericarditis, appendicitis, pulmonary microabscesses, septic arthritis, and fever of unknown origin. These infections could be causative or being consequential, caused by transient bacteremia arising from necrotic tumors seeded in distant organs. In fact and in some instances these unusual and distant infections are the sole clue to the presence of such malignancy. (29) Other than these unusual infections or opportunistic infections, common bacteria and viruses such as Helicobacter pylori and Human papillomavirus have also been reported to be associated with colorectal cancer. But it is not yet clear if these infectious agents are causative or complications superimposed on damaged colorectal epithelium in inflammatory or traumatized bowel conditions as with commensal microbes. (30-1)

Traumas, constipation & diet:

Physical traumas as in the case of anal intercourse in homosexual men, as discussed above (28), and constipation that causes repeated pressure an trauma to the colorectal lumina could damage the colorectal epithelium and colonocytes, cause inflammation and vulnerable to opportunistic infections, hence initiating an oncogenic process. Constipation and laxative use in large sample studies have been shown to increase the risk of colorectal cancer up to 2-3 times, more so in the distal parts of colon and even in younger age groups. (32-3) Indeed as discussed earlier and has been shown in many studies, diet high in meat, proteins and fat, are chemically traumatic to the colonal epithelium and cells and oncogenic promoting, while diet high in fibers are protective. Colon cancer that has been rare in the past, and still rare in developing countries, in fact partly accounts for the diet high in proteins and fat and low in fiber. These hard diets cause higher concentrations of fecal bile acids and sterols, longer transit time, in favor the production of potentially carcinogenic metabolites. (34) As explained earlier, the aging of the colorectal epithelium and colonocytes, decrease in immunity, physical activities and bowel motility as we age all add up to the higher risk of colorectal cancer in case of any traumas, infections or inflammations.

Epigenetic Cancerous Machine:

As discussed, the hereditary cause of colorectal cancer is very minute and only 5-25%. Indeed the colorectal cancer is a very good example of epigenetic mechanism (or environmental impact) of oncogenic production. Most colorectal cancers that occur sporadically arise from gradual mutations in genes regulating cell growth and DNA repair of the large bowel initiated by epigenetic factors, detailed above. Genetic mutations followed by clonal selection result in the transformation of normal cells into malignant derivatives. For example microbial invasions such as commensal bacteria may convert dietary procarcinogens into DNA damaging agents (e.g., ethanol and heterocyclic amines) or directly generate carcinogens (e.g., fecapentaenes). Commensal bacteria alter the epithelial redox environment, such as production of oxygen radicals by Enterococcus faecalis or production of hydrogen sulfide by sulfate-reducing bacteria, all leading to colonic epithelial cell DNA damage, and production of cancer. (35)

In case of inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease, that carry the higher risk of colorectal cancer, the chronic inflammation is believed to promote carcinogenesis, by promoting sporadic colonic chromosomal instability, microsatellite instability, and DNA hypermethylation. The longer the duration andanatomic extent of these colitis and presence of other inflammatory disorders (such as primary sclerosing cholangitis) increase such oncogenic risk, whereas anti-inflammatory drugs, such as mesalamine and steroids, may reduce such risk.

Unlike the normal colonic mucosa, cells of the inflamed colonic mucosa have these genetic alterations before there is any histologic evidence of dysplasia or cancer. Reactive oxygen and nitrogen species produced by inflammatory cells can affect regulation of genes that encode factors that prevent carcinogenesis (such as p53, DNA mismatch repair proteins, and DNA base excision-repair proteins),transcription factors (such as nuclear factor-κB), or signaling proteins (such as cyclooxygenases). Administration of agents that cause colitis in healthy rodents or genetically engineered, cancer-prone mice accelerates development of colorectal tumors. Mice genetically prone to inflammatory bowel disease also develop CRC, especially in the presence of bacterial colonization. (36)

 Genetic or acquired (that is the case in majority) the cancer machine starts with “mutations” in genes such as “APC protein” that normally prevents the accumulation of β-catenin protein that activates the proto-oncogenes or precursors of cancer cells. The mutation(s) could happen in other guts proteins such p53, BAX, TGF-β, SMAD, KRAS, RAF, P13K that normally monitor cell division or protect the gut cells. (37-8) The epigenetic alterations in colon cancers are more frequent and affect hundreds of genes, mostly through “microRNAs targeting protein coding genes and reduce their expression. This is a frequent early epigenetic event in colorectal carcinogenesis, occurring in 81% of colon cancers and in 14% of the normal appearing colonic mucosa adjacent to the cancers. (39-40) In addition to epigenetic alteration of expression of miRNAs, other common types of epigenetic alterations in cancers that change gene expression levels include direct hypermethylation or hypomethylation of CpG islands of protein-encoding genes and alterations in histones and chromosomal architecture that influence gene expression. As an example, 147 hypermethylations and 27 hypomethylations of protein coding genes were frequently associated with colorectal cancers. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers. In addition, 11 hypermethylations and 96 hypomethylations of miRNAs were also associated with colorectal cancers. Recent evidence indicates that early epigenetic reductions of DNA repair enzyme expression likely lead to the genomic and epigenomic instability characteristic of cancer. (41-2)

 Lastly P53, a protein encoded by the TP53 gene, and crucial in controlsing cell cycle and preservation of genome stability, at the time of replication errors or mutations, stops or slows down the cell cycle and points out the DNA damage to the caretakers for repair. If DNA damage is too extensive to be repaired, p53 induces apoptosis (cell death) by shutting down mitochondrial function. The mutation in the tumour suppressor gene p53 is crucial for carcinogenesis to enter from non-invasive to invasive disease. p53 mutations are found in 5% of adenomas, 50% of malignant polyps and 75% of invasive colorectal cancers with a increasing frequency correlating to the extent of malignancy. (43-4)

 Conclusions:

The killer cancer of the west, or the colorectal cancer, seems to have more and obvious epigenetic risk factors of all the cancers and even autoimmune disorders, as the colon or large bowel is the seat of more microbiomes than the rest of the other organs of the body. These epigenetic risk factors are not solely the infective agents or microbial invasions, or even latent infections like other malignancies and even neuro-developmental, psychiatric or neurologic disorders, posted on this site. Perhaps the roe of diet is one of the most important of all in the causation of colorectal cancer by general scientific consensus. The unhealthy diet of high proteins and fats and low fibers, that slows down the motility of the large bowel, gives way to constipation and producing toxins such as ammonia and else, specially in aging population, in a chain of pathophysiologic events, lead to inflammation of the gut and the growth of commensal and opportunistic bacteria at the cost of protective bowel microbiome, immunity, and the guardian of the genome, such as p53.

 Therefore after all, one of the major cancer killers of the humans, could be tamed and the morbidity and mortality could be significantly reduced. We cannot stay young and cannot stop aging, but we could stay active, so to improve the bowel motility and have less constipation. We need also in the rich West, control our diet and reduce the proteins (meats, specially beef and pork), fats and increase the fiber in our diet. This way, we would help the natural micorbiome of the gut and fight against the un-natural growth of opportunistic infections of the bowel, reduce inflammation and at the end lower the risk of colorectal carcinogens. Susceptible individuals such as subjects with inflammatory bowel diseases, and any other bowel pathologies such as polyps, diverticulitis, etc. need to be closely monitored and perhaps the use of more healthy diet and anti-inflammatory agents such as Aspirin be encouraged and prescribed.

Dr.Mostafa Showraki, MD, FRCPC                                                                  Lecturer, School of Medicine, University of Toronto,Author: “ADHD:Revisited” Book/ “adhdrevisited.com”/”medicinerevisited.com”

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