Cancer
What is Colorectal Cancer? PDF Print E-mail

The digestive system is a long tube extending from the mouth at one end the anus (bottom) at the other end. The purpose of the digestive system is to break down food that is eaten so that energy and nutrients can be absorbed into the body. It also plays a role in absorption of water and the excretion of some waste products from the body.

The digestive system is divided into many parts along its length. Food which is taken into the mouth is chewed to help to break down the food. It is then swallowed and passes down the oesophagus to the stomach. In the stomach the food is broken down even more with the addition of digestive juices. After being in the stomach the food then passes into the small bowel where all the energy and nutrients are absorbed into the blood stream. Any non-absorbable contents of the small bowel pass into the large bowel. This is where water is absorbed into the body to make the contents of the bowel more solid. the solid contents is finally stored as a stool in the rectum until this is excreted out of the body through the anus when you go to the toilet.

Diagram of the digestive system

The whole of the bowel is lined by epithelial calls which are a protective coating to the bowel wall. These cells are programmed to constantly replicate and produce new cells as old cells are eroded from the inner edge of the bowel. This replication is a very tightly regulated system, but sometimes damage to the regulation system can cause it can go wrong and cause more new cells to develop than are needed. If this happens then a small stalked outgrowth will develop from the bowel wall, this is called a polyp. Polyp's in themselves are harmless and will not cause any problems. However if they continue to grow they have the potential to develop into a cancer. This means that if any are seen at a colonoscopy then they will be removed.

If the polyp continues to grow then it can develop into a cancer. When this happens the cells are no longer acting as "normal" bowel cells but are replicating in an uncontrolled manner. Also the cells develop the ability to invade into other tissue such as other structures nearby, or distant organs through the blood or lymphatic systems. As well the cells develop immortality where they no longer will die; this is part of what makes treatment of cancer so difficult.

 
Incidence PDF Print E-mail

Cancers are amongst the commonest causes of death in this country, accounting for about one in every four deaths - almost 130,000 per annum1.  The majority of cancer deaths are from tumours found in four principal sites: lung, colorectal, breast and prostate (Figure 1).

UK Surgeon Cancer Incidence

Figure 1. Cancer deaths in England and Wales by sex, 1996.

 

These cancers are common in Western countries but there is a much lower incidence in third world countries (Figure 2).  It has been observed that immigrants moving from a low risk area to one of high risk acquire the same risk as the indigenous population within one or two generations suggesting that environmental factors are responsible2.

 

UK Surgeon Geographic Variation in Colorectal Cancer Incidence

Figure 2. Geographic variation in the incidence of colon and rectal cancer in men 2.

 

Tobacco smoking, electromagnetic radiation, environmental chemicals, hormones, bacterial or viral infection, level of physical activity, reproductive and sexual behaviour are thought to be important in the aetiology of cancer at certain sites3.  However, it is thought that diet remains the most important factor and it has been estimated that dietary change could result in a reduction of fatal cancers of between 35 and 70%4.

Colorectal cancer is the second most common cause of death from cancer in the Western world.  In 1985, there was estimated to be 677,500 new cases and 394,100 deaths worldwide5,6.  In the United Kingdom there is approximately a 4% lifetime risk, 31,000 new cases annually and 16,000 deaths7.

 

The prevalence increases with age with over 90% of cases occurring after the age of 55 (Table 1).  The  incidence of colon cancer varies little between the sexes8,9, whereas rectal cancer is twice as common in men as in women2.

 

Age (Years)

All colorectal cancers

(% of total)

Estimated distal bowel cancer

(% of all colorectal cancers)

<40

345 (1)

200 (58)

40 - 49

1071 (4)

707 (66)

50 - 54

1119 (4)

750 (67)

55 - 59

1986 (7)

1350 (68)

60 - 64

3083 (11)

2096 (68)

65 - 69

4006 (14)

2644 (66)

70 - 74

4710 (17)

3014 (64)

75 - 79

5068 (18)

3041 (60)

³ 80

6605 (24)

3302 (50)

Total

27994

17104 (63)

Table 1. New Diagnoses of Colorectal Cancer by Age, U.K., 1987.10

 

 

 
Colonic Polyps PDF Print E-mail

The pre-malignant lesion: the adenomatous polyp

 

There is abundant evidence that virtually all colorectal carcinomas begin as adenomatous polyps. 

 

In a number of studies, colonic polyps have been left in situ and the follow up of these patients showed variable natural history from complete regression, increase in size or progression to carcinoma11-13.

 

Histological studies have revealed a spectrum of dysplasia within adenomatous polyps up to carcinoma-in-situ and it is not uncommon for true invasive carcinomas to have associated adenomatous tissue14.  In a study of post mortem examinations of the colon, the population with the highest proportion of adenomas was observed in the area with the highest incidence of colonic cancer. Also, the segmental distribution of adenomas within the colon was found to be similar to the site distribution of cancer15.

 

The transition from benign adenoma to colorectal cancer is thought to have a long natural history of between 10 and 35 years 13,16.  It is estimated that the annual conversion rate of a polyp to a cancer is approximately 0.25%17.

 

The adenoma / carcinoma sequence

 

Colorectal carcinogenesis has long been thought to be due to a stepwise accumulation of cellular mutations18.  Studies of adenoma and carcinoma cell types have revealed that there is a monoclonal expansion of a single or small number of colonic epithelial cells19,20.  Much research has been done to identify mutations in oncogenes, tumour suppressor genes or DNA repair genes that confer a growth advantage in these neoplastic cells21.

 

A genetic model for the sequence of adenoma transformation to carcinoma was proposed by Vogelstein22 which in light of recent advances in molecular genetics has become modified to include additional genes that contribute (Figure 3).

 

UK Surgeon Adenomatous Polyps
 
Figure 3. Genetic model of colorectal carcinogenesis

 

It is thought to be the accumulation rather than the order of genetic mutations that is critical to the development of colorectal cancer23.

 

Cellular hyperproliferation is a preceding step to adenoma formation and is associated with loss or mutation of both alleles of the adenomatous polyposis coli (APC) gene on chromosome 5q24.  Inherited mutation in this gene gives rise to familial adenomatous polyposis (FAP) which is typified by hundreds and occasionally thousands of adenomatous polyps25.  The APC gene is a tumour suppressor gene which prevents uncontrolled epithelial cell proliferation.  Mutation results in a truncated APC protein that fails to bind to ß-catenin, which in turn fails to promote cell adhesion via the calcium dependent cell surface adhesion molecule E cadherin 26.

 

The over expression of the cyclo-oxygenases (COX 1 and COX2) catalyses the conversion of arachidonic acid to prostaglandin H2 and other derivatives, e.g. malondialdehyde, which is itself mutagenic, promoting further polyp proliferation 27This explains why the non-steroidal anti-inflammatory drugs, which inhibit the cyclo-oxygenases, have been postulated as possessing a potential therapeutic role in the prophylaxis of colorectal cancer 28.

 

A significant loss of DNA methyl groups has been shown to occur early in colorectal tumourogenesis29.  Hypomethylation interferes with chromosome precipitation and mitotic separation30 resulting in increased frequency of  genetic alterations.

 

Approximately 50% of colorectal cancers31,32 and adenomas larger than 1cm22 have been found to exhibit mutation in the K-ras oncogene.  This mutation is present from the intermediate stage (>1cm, mild & moderate dysplasia) of adenoma formation and therefore probably represents an initiating stage for adenoma progression21.

 

Allelic and chromosomal losses occur frequently in colorectal cancer33,34.  This can result in loss of regions that code for tumour suppressor genes.  Allelic loss of chromosome 18q occurs in more than 70% of carcinomas22 and 50% of late adenomas.  In this area, the tumour suppression gene DCC (deleted in colorectal cancer) is located.  This gene encodes a cell surface-localized protein35 and is thought to be involved in cell adhesion36 and its preservation is associated with the majority of mucinous colorectal tumours37 suggesting a function in cellular differentiation or phenotype modulation.

 

Similarly, the p53 gene located on chromosome 17p38 frequently exhibits allelic loss (also termed loss of heterozygosity).  This occurs in approximately 75% of cases of colorectal cancers22,39 but infrequently at the adenoma stage40.  In addition, somatic mutations in the remaining p53 allele have been regularly observed in keeping with the proposed function of p53 as a tumour suppressor gene38,41.  Thus, mutation in one allele coupled with loss of the other appears to be tumourogenic and an important step in the transformation of adenoma to carcinoma.

 

 
<< Start < Prev 1 2 3 4 Next > End >>

Page 1 of 4