Chapter 3: Colon Cancer
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Colon Cancer
Colon cancer associated transcript 2 (CCAT2) is an lncRNA highly overexpressed in cancer cells that induced the expression of MYC and Wnt signaling targets.
From: International Review of Cell and Molecular Biology, 2016
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Colon Cancer
Brian G. Czito, ... Christopher G. Willett, in Clinical Radiation Oncology (Fourth Edition), 2016
Clinical Manifestation, Patient Evaluation, and Staging
Colon cancer often produces minimal or no symptoms, emphasizing the need for screening programs in the general population. Many colon cancer symptoms are nonspecific, including changes in bowel habits, weakness, intermittent abdominal pain, nausea, and vomiting. The persistence of such symptoms as well as any evidence of iron deficiency anemia should be investigated.
The clinical presentation of colon cancer is determined largely by site of the tumor. Cancers of the right colon are often exophytic and commonly associated with iron deficiency anemia as a result of occult blood loss. During the past 20 years, the relative incidence of right colon cancers has increased and accounts for one third of large-bowel cancers. Many of these are diagnosed late.2 Cancers of the left colon and sigmoid colon are often deeply invasive, annular, and accompanied by partial obstruction and rectal bleeding.
For patients undergoing resection, preoperative evaluation should include pathological confirmation of adenocarcinoma, colonoscopy to evaluate extent of tumor and rule out synchronous primaries (occurring in 3% to 5% of patients), baseline blood counts with liver function tests, and CEA levels. Patients should undergo chest, abdominal, and pelvic CT scan to evaluate extent of locoregional disease as well as the presence or absence of distant metastases. PET scan, MRI, and ultrasound may be useful in evaluating patients with oligometastatic disease who may be appropriate candidates for resection of metastatic disease with curative intent. Figure 50-1 shows a diagnostic algorithm of the management of patients with potentially resectable colon cancer.
Prognostic factors influencing survival in patients with colon cancer include depth of tumor invasion into and beyond the bowel wall, the number of involved regional lymph nodes as well as the presence or absence of distant metastases. The TNM system of the American Joint Committee on Cancer (AJCC) can be used as a clinical (preoperative) or postoperative staging system (Tables 50-1 and 50-2). Additionally, site-specific prognostic factors have been identified and are included in the AJCC staging form (Box 50-1).
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Colon Cancer
LEO TREYZON, ... DAVID HEBER, in Nutritional Oncology (Second Edition), 2006
CONCLUSION
Colon cancer is a diet-related cancer. Most incident colon cancer is preventable through modulation of nutritional choices over a lifetime. As far as this disease is the second leading cause of cancer death in the United States, with >56,000 projected deaths in 2005, it represents a high-priority area for further investigation. Survival remains poor because most cases are diagnosed at an advanced stage. The existing strategies for CRC prevention include dietary prevention, chemoprevention, and endoscopic prevention. Although distal colon polyps are poor predictors of subsequent polyp and cancer in the upper colon, the finding of a polyp should motivate changes in lifestyle and diet.
The main nutritional factors believed to influence the risk of this disease include obesity, increased red meat intake, calcium, vitamin D, folic acid, alcohol, fiber, phytonutrients, and dietary fatty acids. Epidemiological studies have also uncovered interesting interactions among nutrients such as alcohol and folic acid, which affect colon cancer risk.
Although the relative contributions of these individual dietary factors on colon carcinogenesis are still in question, it remains clear that healthy nutritional choices constitute the main prescription for colon cancer prevention at the societal level. Insofar as the prescription for avoidance of these harmful constituents and consumption of the beneficial ones is associated with prevention of other chronic diseases such as atherosclerotic heart disease, it can be assumed that there are health benefits that this prescription carries beyond colon cancer prevention.
The Vogelstein model for multistep colon carcinogenesis has provided insights into the epigenetic changes that occur in the process and has provided molecular targets for cancer prevention strategies. Nutritional factors have been shown to be effective at ameliorating transition at each of these steps.
Studies of families at increased risk of colon cancer have led to the discovery of inherited abnormalities of DNA mismatch repair enzymes and even to common genetic polymorphisms of metabolic enzymes such as GSTM1, which may affect individual responses to preventive phytochemicals. These nutrigenetic models in combination with the emerging evidence on nutrigenomics of phytochemicals in the colonic epithelium promise to provide important new insights helpful in designing strategies for colon cancer prevention through changes in diet and lifestyle.
Carcinomas of the colon appear to be partially preventable by diets rich in fruits and vegetables. Plant foods contain a variety of components including micronutrients, PUFAs, and secondary metabolites such as glucosinolates and flavonoids, many of which can inhibit cell proliferation and induce apoptosis and may act synergistically when combined in the human diet.
The challenge is to fully characterize and evaluate these effects at the cellular and molecular level to exploit their full potential as protective mechanisms for the population as a whole. The power of early diagnosis via colonoscopy, fecal DNA analysis, and the preventive potential of healthy diets and lifestyles should lead to further decreases in incident colon cancer.
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Vitamin D and Colon Cancer
Antonio Barbáchano, ... Alberto Muñoz, in Vitamin D (Fourth Edition), 2018
Abstract
Colon cancer is one of the most frequent and lethal neoplasias and the first to be associated with vitamin D deficiency. Many epidemiological studies indicate a protective effect of vitamin D on colon cancer. This is supported by preclinical studies using vitamin D, 1,25(OH)2D3 or analogues in cultured cells and experimental animals. These compounds regulate colon carcinoma cell gene expression, survival, differentiation, proliferation and invasion and inhibit angiogenesis and metastasis during colon cancer progression. Remarkably, in animal and in vitro models vitamin D compounds inhibit the Wnt/β-catenin signaling pathway, whose aberrant activation initiates and maintains colon cancer. Moreover, recent data show that 1,25(OH)2D3 protects against colon cancer acting also on tumor stromal fibroblasts. However, clinical data are scarce and inconclusive, and a definitive answer about the role of vitamin D compounds in the prevention and treatment of colon cancer requires new, large, well-designed clinical trials.
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Azoxymethane-induced Colon Carcinogenesis through Wnt/beta-catenin Signaling and the Effects of Olive Oil
Takehiro Fujise, ... Kazuma Fujimoto, in Olives and Olive Oil in Health and Disease Prevention, 2010
Colon cancer is one of the leading causes of cancer death in both men and women in Western countries, and in recent years, it has increasingly become a major cause of cancer mortality in Oriental countries, including Japan. These changes are associated with the westernization of Japanese dietary habits, which involves high consumption of meat and fat, together with low consumption of fruit, vegetables, vitamins and fibers, compared with classical Japanese diets. In fact, many epidemiological studies have shown a positive relationship between dietary fat consumption and colorectal cancer. Cancer results from the accumulation of multiple independent genetic alterations. In colon cancer, these genetic changes affect colon epithelial cell proliferation, differentiation and apoptosis. In familial adenomatous polyposis (FAP), which is one of the hereditary forms of colon cancer, a gene has been identified and its protein is a key molecule in the Wnt signaling pathway. Many experiments have shown that the Wnt signaling pathway plays a crucial role in the etiology of colon cancer, including hereditary and sporadic forms. This chapter focuses on dysregulation of colonic mucosal homeostasis in carcinogen-induced colon cancer models and the effects of dietary fatty acid.
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Polyphenols in the Prevention and Treatment of Vascular and Cardiac Disease, and Cancer
Swapnil M. Chaudhari, ... Sachin L. Badole, in Polyphenols in Human Health and Disease, 2014
6.3 Colon Cancer
Colon cancer is the third most common cancer in men and the second in women. Worldwide, an estimated 1.2 million cases of colorectal cancer occurred in 2008.24 The number of azoxymethane-induced aberrant crypt foci in rats, an animal model for colon cancer, was significantly decreased by consumption of pomegranate juice47 and punicic acid-rich pomegranate seed oil.48 Additionally, in human colon (HT-29, HCT116, SW480, SW620) cell cultures, pomegranate juice inhibited proliferation and induced apoptosis,28 possibly via an inflammatory cell signaling mechanism.49 Punicalagin, the primary ellagitannin in pomegranate, was shown to release ellagic acid in cell culture media, which actively induced apoptosis of colon cancer-derived Caco-2 cells.50 It has also been shown that specific ellagitannins from pomegranate and the corresponding urolithin metabolites inhibited proliferation and induced apoptosis of HT-29 human colon cancer cells.51,52 Moreover, pomegranate seed oil extract rich in conjugated linolenic acid suppresses colon carcinogenesis in rats.38,53 Further investigations need to be carried out.
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Physical Activity and Health
G.A. Colditz, ... C.T. Ryan, in International Encyclopedia of Public Health, 2008
Colon cancer
Colon cancer is the second leading cause of cancer-related death in the United States. However, the risk of developing colon cancer can be reduced through a number of lifestyle factors, with physical activity being one of the most important. Among both men and women, high levels of physical activity may lower the risk of colon cancer by as much as 50% (Colditz et al., 1997). Although studies have not consistently used a standard measure of activity or defined exactly what constitutes a 'high' level of activity, a dose–response relationship has been observed consistently across a variety of study designs and populations. In addition, this relationship has been observed across a wide range of weights, which suggests that the effect of physical activity on colon cancer incidence is independent of the effect of obesity.
Although maintaining a high level of physical activity throughout life appears to impart the greatest protection against colon cancer, this does not mean that sedentary people cannot reap the benefits if they become active. In a hallmark study by Lee et al., men who were sedentary at baseline and became active during the study had a 13% lower risk of colon cancer than men who were sedentary at baseline but remained so (Lee et al., 1991). In addition, the level of activity needed to reduce colon cancer risk appears moderate. Data from at least two prospective studies, conducted by Giovannucci and Martinez, indicate that both men and women can lower their risk of colon cancer by simply engaging in moderate physical activity, such as brisk walking or stair climbing, for 1 h per day (Giovannucci et al., 1995; Martinez et al., 1997). For participants whose only recreational activity was walking, there was a dose–response relationship between risk and walking pace: the faster they walked, the lower their risk was. For each additional hour of brisk walking per week, risk was reduced by approximately 10%.
Several mechanisms have been proposed to explain the link between activity and colon cancer. First, vigorous physical activity may lessen the amount of time that it takes stool to pass through the colon, thereby minimizing contact between the colon wall and any potential carcinogens in the stool. Second, physical activity may reduce circulating levels of insulin, which is a growth factor for colonic epithelial cells. Finally, additional hypotheses suggest that physical activity may alter prostaglandin levels, improve immune function, and modify bile acid metabolism.
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Physical Activity and Health
Graham A. Colditz, ... Hank Dart, in International Encyclopedia of Public Health (Second Edition), 2017
Colon Cancer
Colon cancer is the second leading cause of cancer-related death in the United States. It is, however, very preventable. The risk of developing colon cancer can be reduced through a number of lifestyle factors, with physical activity being one of the most important. Among both men and women, high levels of physical activity may lower the risk of colon cancer by 30% (Lee, 2003). Although studies have not consistently used a standard measure of activity or defined exactly what constitutes a 'high' level of activity, a dose–response relationship has been observed consistently across a variety of study designs and populations (Figure 1). In addition, this relationship has been observed across a wide range of weights, which suggests that the effect of physical activity on colon cancer incidence is independent of the effect of obesity. Other studies examining colon adenomas and polyps also indicated a decreased risk with increasing physical activity. However, no association was found for rectal cancer (Friedenreich et al., 2006; Wolin et al., 2011).

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Figure 1. Physical activity level and risk of colon cancer.
Data source: Wolin, K.Y., Yan, Y., Colditz, G.A., Lee, I.M., 2009. Physical activity and colon cancer prevention: a meta-analysis. Br. J. Cancer 100 (4), 611–616.
Although maintaining a high level of physical activity throughout life appears to impart the greatest protection against colon cancer, this does not mean that sedentary people cannot benefit from becoming active. In a hallmark study by Lee et al., men who were sedentary at baseline and became active during the study had a 13% lower risk of colon cancer than men who were sedentary at baseline but remained so (Lee et al., 1991). In addition, the level of activity needed to reduce colon cancer risk appears moderate. Data from at least two prospective studies, conducted by Giovannucci and Martinez, indicate that both men and women can lower their risk of colon cancer by simply engaging in moderate physical activity, such as brisk walking or stair climbing, for an hour a day (Martinez et al., 1997; Giovannucci et al., 1995). For participants whose only recreational activity was walking, there was a dose–response relationship between risk and walking pace: the faster they walked, the lower their risk was. For each additional hour of brisk walking per week, the risk was reduced by approximately 10%.
Several mechanisms have been proposed to explain the link between activity and colon cancer. First, physical activity may lessen the amount of time that it takes stool to pass through the colon, thereby minimizing contact between the colon wall and any potential carcinogens in the stool. However, studies looking at this potential mechanism have had mixed results (Cho et al., 2013). Second, physical activity may reduce circulating levels of insulin, which is a growth factor for colonic epithelial cells. Finally, additional hypotheses suggest that physical activity may alter prostaglandin levels, improve immune function, and modify bile acid metabolism.
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Garcinol: Preclinical Perspective Underpinning Chemo- and Radiosensitization of Cancer
Sanjeev Banerjee, ... Shivani B. Paruthy, in Role of Nutraceuticals in Cancer Chemosensitization, 2018
Garcinol and Colon Cancer
Colon cancer begins as a small polyp and diagnosed in more than 130,000 people in the United States alone despite screening drive accounting for a 30% drop in colon cancer rate and increasing 5-year survival rate by 65%. Current treatment options for colon cancer include the combination of a variety of chemotherapeutic drugs, especially the third generation of platinum-based drug-oxaliplatin plus 5-fluorouracil and leucovorin (referred to as FOLFOX). Other options include oxaliplatin plus capecitabine (Xelox) or oxaliplatin plus cetuximab (CAPOX). Unfortunately, no studies have yet been reported on the chemosensitization efficacy of garcinol with any platinum class of compounds in colon cancer. Nevertheless, garcinol facilitates protection against dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced inflammation-related colon tumorigenesis in mice [10]. In these investigative models, garcinol prevented shortening of the colon length and the formation of aberrant crypt foci (ACF) and improved the inflammation score in the colon stimulated by DSS [10]. Additionally, dietary administration of garcinol (250 and 500 ppm) efficiently reduced the tumor size and incidence in the mouse colon. The finding applauds that garcinol merits further clinical investigations as a chemoprophylactic agent that may help prevent colitis-associated colon cancer. Also from the chemoprevention perspective, it has been noted that dietary garcinol significantly reduces the percentage of large ACF (comprising of four or more aberrant crypts, 26% and 40% reduction at a dose of 0.01% and 0.05% garcinol in diet) in AOM-induced colonic ACF, alongside significantly lowering the PCNA index in ACF, and in "normal-appearing" crypts with their ability to prevent ACF [18]. Such situations, regarding the number of ACF consisting of four or more aberrant crypts, correlate with the incidence of colonic adenocarcinoma induced by colonic carcinogen-AOM. However, a long-term bioassay is warranted in view of reports in the literature indicating that certain compounds that reduce the number of ACF and reduce proliferation may not necessarily inhibit the formation of colon tumors. Other specific targets of garcinol in colon cancer involve the modulation of tyrosine phosphorylation of FAK and subsequent induction of apoptosis through downregulation of Src, ERK, and Akt survival signaling in human colon cancer cells [48]. As reported earlier, FAK is the major signaling mediator of integrin-mediated cell-matrix contact-regulated cellular proliferation and migration and subsequently induces apoptosis in adherent cells.
Sulindac, a nonsteroidal anti-inflammatory drug (NSAID), has shown efficacy in preventing colorectal cancer [80,81]. Contextually, growth inhibitory and synergistic effects of Garcinia benzophenones combined with sulindac on human colon cancer cells have been reported [82]. Guttiferone E reportedly exhibits synergy with the NSAID sulindac sulfide [82]. These findings indicate the potential of Garcinia sps benzophenone, alone or combined with sulindac sulfide, in the treatment strategy of colon cancer.
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MICROFLORA OF THE INTESTINE | Role and Effects
B.R. Goldin, in Encyclopedia of Food Sciences and Nutrition (Second Edition), 2003
Colon Cancer
Colon cancer is a common disease in Western Societies. Epidemiological studies have shown that the incidence of colon cancer is higher in North America and Western Europe than in Africa, Asia, and South America. A number of studies have shown a positive correlation between consumption of beef, fat, and protein, and a negative correlation with fiber, and the incidence of colon cancer. It has been proposed that the dietary influence on the etiology of colon cancer results, in part, from alteration of the metabolic activity of the intestinal microflora, more specifically, the ability of intestinal bacteria to convert procarcinogens to proximate carcinogens. This conversion would be greatest in the large bowel where the bacterial population is highest, and the transit time for the fecal stream is the slowest. Several bacterial enzymes have been implicated in the formation of mutagens, carcinogens, and tumor promoters. Among the enzymes that have the potential to increase the incidence of colon cancer are: β-glucosidase, β-glucuronidase, β-galactosidase, azoreductase, nitroreductase, 7-α-steroid dehydrogenase, and 7-α-hydroxy-steroid dehydroxylase.
There have been at least five different classes of mutagens isolated in the feces that have the potential to cause colorectal cancer. The final step in the synthesis of fecapentenes (dodecapentaenyloxy-1,2 propanediol), one class of mutagen, involves the action of the intestinal flora.
Bile acids, particularly the secondary bile acids, can act as colon tumor promoters, and, as discussed previously, the fecal microflora are responsible for the generation of secondary bile acids in the colon.
Heterocyclic aromatic amines are also procarcinogens, which can be acted on by bacterial and intestinal tissue enzymes to generate proximal carcinogens. Nitrosamines, which are also present in the colon, are often direct-acting and spontaneously breakdown to electrophiles, which react with DNA and do not require activation by bacteria or tissue enzymes. The final broad class of known potential colon carcinogens are polycyclic aromatic hydrocarbons, which are generally activated by tissue microsomal enzymes. From this brief discussion, it is apparent that the intestinal flora can be an important factor in the etiology of colon cancer.
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