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It is generally accepted that the vast majority of colorectal cancers arise from benign tumours, termed adenomas (Bussey, 1975; Hermanek et a l , 1983). Cell kinetic studies involving in situ DNA labelling of colonic epithelial cells have demonstrated that the proliferative zone, which is confined to the lower two-thirds of the crypts of Lieberkuhn in normal colorectal mucosa, is shifted to the surface of the crypts in adenomas and in adjacent mucosa (Deschner and Lipkin, 1975). Further evidence suggests that widespread hyperproliferation of the colorectal mucosa precedes the development of colorectal carcinoma (Ponz de Leon et a l, 1988).

Histologically adenomas are divided into tubular, villous and tubulo-villous adenomas. Tubular adenomas (also known as adenomatous polyps) are the most common type, and are composed of branching tubules embedded in the lamina propria. Villous adenomas are composed of finger-like processes of lamina propria covered by epithelium reaching down to the muscularis mucosae, and tubulo-villous adenomas have a histology intermediate between tubular and villous (Bussey, 1975; Muto et a l, 1975). Tubular and villous adenomas are not separate entities but represent two extremes of a histological spectrum of tumours that are essentially part of the same neoplastic process (Bussey, 1975).

A gradual transition from benign to malignant tumour is suggested, associated with increasing size of adenoma and grade of dysplasia (Morson, 1974; Muto et a l,

1975; Fearon and Vogelstein, 1990). Villous adenomas have the highest malignancy rate. The histological distinction between an adenoma with severe dysplasia and an

adenocarcinoma is infiltration through the muscularis mucosae into the submucosa (Morson, 1974; Hermanek e t a l , 1983).

More recent studies suggest that microscopic epithelial lesions called dysplastic aberrant crypt foci (ACF) are the precursors of adenomas, and therefore the earliest identifiable precursors of colorectal neoplasia (Pretlow et al., 1991; Roncucci

et a l, 1991; Jen et a l, 1994b). ACF are composed of clusters of abnormally large dark staining slightly elevated mucosal crypts.

1.2.5. Aetiology

The high incidence of colorectal cancer in industrialized nations is considered by some to be related to a 'Western' diet, with high fat and meat consumption and low fibre intake (Wynder and Shigematsu, 1967; Burkitt, 1971), but the evidence is not conclusive. For example while some case-control studies support a strong positive association between total dietary fat intake and colorectal cancer risk, others report no significant association (Willett, 1989). The type of fat (eg. animal fat) rather than the total amount may be the important factor. Mechanisms for how fat is involved in colorectal carcinogenesis have been proposed: high levels of dietary fat result in an increased concentration of bile acids and cholesterol in the gut and modify the activity of gut bacteria. The bacteria convert these substances into secondary bile acids and cholesterol metabolites, which are thought to act as tumour promoters (Hill

et a l, 1971; Reddy, 1981). Secondary bile acids enhance epithelial cell proliferation in the large bowel (DeRubertis et a l, 1984).

Burkitt (1971) suggested how fibre may protect against bowel cancer by hypothesizing that a higher dietary fibre intake increases the stool bulk and speed of transit, diluting potential carcinogens and reducing their contact with the colonic mucosa. In addition, fibre and resistant starch are substrates for anaerobic fermentation by flora in the bowel which results in the production of short chain fatty acids such as butyrate (Cummings and Bingham, 1987). Sodium butyrate has been shown to inhibit the proliferation of colorectal tumour cells (Augeron and Laboisse, 1984). Fermentation of fibre lowers colonic pH and it has been proposed that this inhibits the conversion of primary to secondary bile acids (Thornton, 1981). Several, but not all, case-control studies report that a reduction in colorectal cancer risk is associated with intake of fibre, mainly from fruit and vegetables (Willett, 1989; Bingham, 1990). However these foods are the main dietary source of certain micronutrients that may have a protective role in colorectal cancer, such as p-carotene and vitamin C (La Vecchia et a l, 1996). Therefore although there is strong evidence

that fruit and vegetables have a protective effect, the responsible factor has not been clearly identified.

Cooked meat contains a number of mutagens and some products of protein metabolism in the gut have been implicated in colorectal carcinogenesis (Cummings and Bingham, 1987), but epidemiological support for involvement of meat intake in colorectal neoplasia is inconsistent (Bingham, 1990). Total calorific intake shows a positive association with colorectal cancer risk (Potter and McMichael, 1986). A reason for the inconsistency between case-control studies described above may be inadequate statistical adjustment for total calorific intake, to determine the specific effect of individual nutrients (Willett, 1989). Other dietary considerations include alcohol consumption, particularly beer which has been linked with rectal cancer (McMichael et al., 1979). High doses of calcium have been shown to significantly reduce epithelial cell proliferation in the colorectum (Wargovich et al., 1992). The mechanism is not clearly known but it has been hypothesized that free fatty acids and bile acids are converted into insoluble calcium compounds, thus mitigating their toxic effects (Newmark e ta l, 1984).

Decreased colorectal cancer risk is associated with the use of nonsteroidal antiinflammatory drugs (NSAIDS) such as aspirin (Thun et al., 1991) and sulindac, which has been found to cause polyp regression in patients with familial adenomatous polyposis (Gonzaga et al., 1985). The antineoplastic effect of NSAIDS is not fully understood, however they are known to inhibit the synthesis of prostaglandins which are thought to be involved in tumour promotion (Verma et a l, 1980), and more recently have been demonstrated to block the cell cycle in the Gq-Gi phase and induce apoptosis in colorectal cancer cells (Shiff et al., 1995; Elder et al, 1996).

The risk of colorectal cancer, particularly that of the colon, is greater in women than in men at younger ages. This risk is reversed postmenopausally, suggesting a hormonal effect (McMichael and Potter, 1983). In addition women have been found to have a slower bowel transit time and reduced stoolbulk compared with men which could contribute to their increased risk (McMichael and Potter, 1983). Finally, a higher risk of colorectal cancer is associated with a previous diagnosis of bowel cancer (Wynder and Shigematsu, 1967), and with other diseases of the bowel including ulcerative colitis (Devroed and Taylor, 1976) and Chrohn's disease (Kuster

e t a l , 1989).

1.2.6. Diagnosis and Treatment

The main symptoms of colorectal cancer are alterations in the frequency of bowel movements and stool consistency, blood and mucous in the stool and diarrhoea. Symptoms generally appear later with right-sided colon tumours as they not as exposed to damage by the stool (Hermanek et al., 1983). The main treatment for colorectal cancer is surgery. Adjuvant chemotherapy is sometimes used especially to treat lymph node métastasés but has not resulted in a significant improvement in survival rates (Hermanek et al., 1983).

Almost half of all patients present at late stage of disease, prognosis is relatively poor with roughly one third of patients surviving to five years after diagnosis (Cancer Research Campaign Factsheet 18, 1993). Screening techniques for the detection of tumours at early stages are being assessed. In the United States it is currently recommended that asymptomatic individuals over the age of 50 at average risk, should be screened with an annual faecal occult blood test and sigmoidoscopy, preferably flexible, every 5 years (Lieberman and Sleisenger, 1996).