Aspirin and Colorectal Cancer

Colon cancer kills 17,000 Britons every year. Many patients with colon cancer have a recurrence after surgery, so that there is a tremendous need for better prevention and treatment. aspirin research is potentially important for its prevention and for developing new therapies. Most colon cancers arise spontaneously, with no obvious inheritance. Eighty per cent of cases arise in people older than 65. However, possessing a single gene defect among the 50,000 genes we possess can give us a 100 per cent risk of bowel cancer. People with these rare mutations belong to one of two types of family - those with familial adenomatous polyposis (FAP) and those with heritable non-polyposis colon cancer (HNPCC).

Cancer is a multistage process. Patients who have the FAP mutation can develop in teenage 500 to 5000 benign tumours (polyps), which are mostly small. Some of them enlarge, and eventually one of these larger polyps becomes cancerous. The process takes 15 to 20 years so that they develop cancer when they are between 30 and 40 years. In sporadic cancer there is also a precancerous stage, but it takes much longer, which is why such patients are much older when their symptoms begin.

The transition from normal cell to cancerous cell is in several stages, involving a series of genes acting one after the other. Those mentioned by Professor Paraskeva included the APC/B-catenin gene that converts normal gut cells into early adenomas. The next stage, to late adenoma, requires a mutation in the K-Ras gene. Even now the tumour will only enlarge locally. Then mutations in P53 and loss of heterozygosity (LOH) in the 18q chromosome allow the cells to spread beyond the gut - to become metastatic. It is vital to prevent that last stage. Obviously many research groups are now trying to find ways to control these genes, to develop ways to prevent and to treat bowel cancer.

Is diet important? There are huge differences in colorectal cancer rates - in India 1.8 per 100,000 develop the disease. The corresponding rate in the United States is 34.1. Changes in dietary habits are causing low incidence countries, such as Japan, to become high. Diet obviously matters. Professor Paraskeva estimates that 50 to 70 per cent of bowel cancers are preventable. We could reduce numbers of deaths in UK from 17,000 to 8,000. Natural diets should contain vegetables and fruit - at least 5 portions per day. By studying chemopreventive agents like aspirin, vitamins and minerals we may be able to replace them with natural diets. We know approximately how they work, and maybe we can replace them with natural foods and diets. We may then be more precise.

The first hint that aspirin and drugs like it such as non-steroidal anti-inflammatory drugs (NSAIDS) might be useful in colorectal cancer arose when patients with benign polyps were given sulindac for pain relief. By chance it was found that their tumours shrank and some even disappeared. When the sulindac was stopped the tumours recurred. Professor Paraskeva suggested that NSAIDs might work by causing the tumour cells to commit suicide.

Regular takers of aspirin for pain and inflammation have a 30 to 50 per cent reduction in their risk of developing bowel cancer. They also have fewer benign tumours (adenomas) in their bowel wall. Professor Paraskeva explained how this happens.

aspirin blocks the action of the enzyme cyclo-oxidase (COX). The main function of COX is to produce a series of substances called prostaglandins (PGs) in the body which are active in inflammation. aspirin blocks this. There are two isoforms of COX. COX-1 is produced by normal cells and protects the stomach wall against acid. COX-2 is not present in most normal cells and not present in normal colon. But COX-2, and therefore prostaglandins, are overproduced by colon cancer cells and by the premalignant adenoma cells. If cells produce too much COX-2 they produce too many prostaglandins.

Cancer cells produce high levels of COX-2, and the high PG levels also increase cell growth, decrease cell death, increase tumour invasion and induce new blood vessels to grow around them ('angiogenesis'). So they become more invasive and spread to other parts of the body. The increase in blood vessels helps the tumour to grow and become more aggressive. aspirin inhibits both the high COX-2 activity and the normal COX-1 activity. Its ability to prevent cancer is in part due to the COX-2 effect.

Professor Paraskeva was in no doubt that when the risks of taking aspirin (a few people may suffer stomach bleeds) are outweighed by its advantages then it should be given. He does not recommend that the general public should take aspirin to reduce their risk of colorectal cancer. For the moment they should take it only as part of a clinical trial in patients who are at high risk of developing colorectal cancer. They include HNPCC patients or patients with a history of colorectal polyps in whom the possible benefits outweigh any possible side effects. He was unclear on how serious the side effects of aspirin are, and whether dose and type of aspirin preparation make a difference to them.

Finally he showed how cells in the tadpole tail commit suicide to allow it to become a frog. In human development, cells in the webbing between fingers also commit suicide. Every second about 10 million cells die naturally from skin, blood cells and the colon as part of normal tissue turnover. They need to be continuously replaced by cell division. Each tissue must not continue to grow beyond what is necessary. Some of the genes that are affected in cancer patients are suicide-inducing cells. Salicylates may well promote cancer cell suicide by reprogramming them. Leaves fall off trees because the cells ate their base commit suicide. This may well be one of the functions of salicylates in plants. There is no reason to think that salicylate could not have a similar effect in animals.

Professor McVie, commenting, mentioned that we now talk about vegetables and fruit in a healthy diet, and not fruit and vegetables. Is this because vegetables contain more salicylates than fruit?

The theme of how aspirin can protect against cancer was continued by Dr Henry Jabbour, Senior Scientist, MRC Human Reproductive Sciences Unit at the University of Edinburgh Academic Centre. He spoke about cervical cancer.