POBLACIÓN Y MUESTRA

1.3. Epidemiology of colorectal cancer.

Cancer o f the colon and rectum shows a significant geographic variation in incidence and is primarily considered a disease of developed industrialised countries (Boyle et aL, 1985). In North America and the United Kingdom it is the most common form o f cancer after lung cancer, with 155,000 new cases per year in the United states alone (Doll and Peto, 1981; Henderson et aL, 1991). The 25,000 new cases o f colorectal cancer reported in the UK annually are ultimately responsible for

19,000 deaths (Northover, 1989).

In genetic terms colorectal cancer has become one o f the best understood forms o f neoplasia. Inherited syndromes that predispose to colorectal cancer have been characterised at the DNA level, and have shed considerable light on the role of various genes and biological processes in the evolution o f this type o f tumour (e.g. Kinzler et aL, 1991; Fishel et aL, 1993). Furthermore, the existence o f a defined premalignant lesion, the adenomatous polyp, allows mutations that occur early in tumour development to be assessed more easily than in many other forms of malignancy (Muto et aL, 1975).

The specific environmental factors underlying the aetiology of malignant disease may vary considerably firom one form of cancer to another. A substantial volume of population data suggests that diet is the principal factor influencing the development o f cancers o f the gastrointestinal tract. The association between colon cancer and diet was originally noticed in an investigation o f cancer incidence in rural South Afiicans (Bantu and Cape), which revealed that they were ten times less likely to develop colon cancer than their North American (both black and white) counterparts (Higginson and Ottle, 1960). That this variation has an environmental and not a genetic basis is evidenced by migrant populations that adopt the colorectal cancer incidence o f their new locality within a single generation (Shottenfeld and Haas, 1978).

The simple high fibre diet of the rural South Africans compared to the higher fat content diet o f the Americans appears to be the most significant difference between the two populations. Burkitt, who found a lower incidence of colon cancers in several agricultural African populations, suggested that the concentration o f carcinogens and the duration o f their contact with the gut would be less if a diet had a high roughage content (Burkitt, 1971). Such diets produce a faster passage o f material through the gut and a larger stool volume. The majority of studies support a protective effect i f fibre against colorectal cancer, however not all studies are in agreement (Wasan and Goodlad, 1996). Indeed most studies in which rodents have been fed significant quantities o f dietary pectin, alfalfa, or guar gum show either an increased rate of colorectal cancer or no effect (Roberfroid et aL, 1993; Hill and Leeds et aL, 1996). This illustrates that the complexity of fibre, which has no universally accepted scientific definition, makes it difficult to deduce its effect on colorectal cancer development. The source of fibre and the proportion of resistant starch compared to non-starch polysaccharides varies considerably between different studies (Trock et aL,

1991). Factors such as total calorific intake and affluence are positively correlated with both colorectal cancer and reduced fibre intake further confusing matters (Armstrong and Doll, 1975).

A less contentious relationship exists between fat intake and risk o f colorectal cancer. That increasingly high levels of fat, animal fat in particular, cause an increase in the chance o f developing colorectal cancer has been well documented (Morgan et aL, 1988; Willet et aL, 1990). Results of epidemiological studies suggest that a 50% reduction in the consumption of animal fat would cause a similar reduction in colorectal cancer risk (Morgan et aL, 1988; Willet et aL, 1990). Mice genetically predisposed to the development of intestinal tumours develop tumours o f increased size and number in response to an increase in fat intake (Wasan et aL, 1997). This feature appears to be independent of total calorific intake. Rodents fed on high fat diets suffer inflammation and superficial lysis o f epithelial cells in the colon. This may be caused by fatty acids and bile acids which irritate the epithelium. Large quantities o f fat in the diet cause excretion of cholesterol and bile acids into the lumen o f the gut. These are metabolised by bacteria in the intestine producing the irritating secondary bile acids, and possibly other carcinogenic polycyclic hydrocarbons as well (Reddy et aL, 1981). Correlation between fat intake and development o f cancer is less

extreme in animals lacking intestinal bacteria, hinting that these micro-organisms do indeed have a role in the tumourigenicity o f fat (Reddy et a/., 1975). Cell loss resulting from this irritation and lysis is compensated for by increased proliferation in the colonic epithelium. This stimulation of cell division may represent the mechanism by which fat increases the risk of colon cancer (Wargovich et aL, 1984; Preston- Martin et aL, 1990). Alcohol, another factor that increases the risk o f colorectal cancer, has also been shown to induce proliferation o f intestinal cells in the rat (Wu et aL, 1987).

It may be that factors which effect the metabolism o f bile acids and fibre can modify their influences on tumour formation. One hypothesis is that raised rates o f bacterial fermentation o f fibre cause a lowering of pH which reduces break down o f bile acids (Thornton, 1981). High levels of calcium and fibre are thought to affect not only the metabolism o f the intestinal bacteria but also the varieties, o f bacteria inhabiting the gut (Cummings and Bingham, 1987). Calcium and some forms o f fibre bind to bile acids and fatty acids and carry them out of the gut. Calcium does this by forming insoluble soaps, while fibre achieves this by physiochemical binding (Newmark et aL, 1984).

As well as dietary factors to counteract the effect o f fats there also exist foods which offer protection against more classic carcinogens. For example, certain families o f vegetables contain small quantities o f indoles which inactivate polycyclic aromatic carcinogens by inducing oxidases (Wattenberg and Loub, 1978). Many aspects of a diet probably act to promote or reduce the development of colorectal cancer. However determining which individual factors are acting at any one time is problematic due to the number o f components in the diet.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as asprin and sulindac have been shown to protect against colorectal cancer (Kune et aL, 1988; Rosenberg et aL, 1991; Thun et aL, 1991). Small doses o f asprin, taken regularly, reduce the incidence o f colorectal cancer (Thun et aL, 1991), while sulindac has been demonstrated to cause regression o f polyps in the large bowel o f patients with familial adenomatous polyposis (FAP) (Gonzaga et aL, 1985; Labayle et aL, 1991). The protective effect conferred by NSAIDs may result from inhibition o f the synthesis o f prostaglandins, which are associated with accelerated tumour progression (Lupulescu,

apoptotic mechanisms in the colonic mucosa (Moser et aL, 1996). Discontinuation o f asprin or sulindac treatment results in a return to a typical risk o f colorectal cancer and, in FAP patients, a recurrence of polyps (Thun et aL, 1991; Labayle et aL, 1991).

Among the other factors known to increase risk of colorectal cancer are alcohol, total calorific intake, sedentary lifestyle, genetic factors (see section 1.5.), and gender (Klatsky et aL, 1988, Graham et aL, 1988, Slattery et aL, 1988, Wynder and Shigematsu, 1967). Increased physical activity which aids peristalsis may reduce risk by increasing the rate of faecal passage through the gut. The fact that women are more likely to develop colorectal cancer than men might be due in part to smaller volumes of faeces and longer passage times through the intestine. However, declining incidence in post-menopausal women is suggestive of an hormonal association. A mechanism by which hormones influence susceptibility may be related to the fact that progesterone increases cholesterol levels in the blood and thereby decreases production of bile acid, while oestrogen has the opposite effect.

1.4. Aetiology of colorectal cancer.

At an anatomical level the colorectum can be subdivided into nine different parts (figure 1.1.). It’s microscopic structure reveals a mucosal surface characterised by invagenated crypts (crypts o f Lieberkuhn) (figure 1.2.). The surface epithelium is predominantly composed o f columnar cells, but also includes abundant goblet cells, particularly in the upper two thirds of the crypt. The lower third of the crypt, in which most cell regeneration and proliferation occurs, contains a majority o f columnar cells with scattered enterochromaffin cells. Cells are produced by mitosis in this proliferative zone, and migrate up the sides of the crypt as they differentiate and mature, ultimately undergoing apoptosis and being shed into the lumen (Deschner,