The Hole Story:
The Mouse Model of Cancer ctd.
Vivienne Reeve became interested in the effect of different types of fat and different levels of fat in the diet 5 or 6 years ago. There is a growing body of literature concerning the role of dietary fat in the development of cancers caused by chemicals in both animals and humans. Dietary fat can particularly influence the development of colon cancers and breast cancers.
Reeve has carried out tests by irradiating mice while feeding the mice both polyunsaturated and saturated fats at high and low levels. The interesting result from this research was that the mice which were not given any polyunsaturated fat did not get skin cancers; they were totally protected from skin cancer.
She also found that as soon as they fed back polyunsaturated fats in a normal diet, the skin cancers appeared on all of the mice. This result indicated that the absence of polyunsaturated fat doesn't prevent the creation of the potential cancer cell in the skin. The cancer cells are initiated but that somehow the absence of polyunsaturated fat interferes with the capacity of those potential cancer cells to grow out into tumours. So an absence of polyunsaturated fat somehow inhibits the whole process of cancer development after sun exposure.
Some experiments done here by my PhD student Melissa Matheson have gone on to try and examine what it is that happens in the later stage that controls whether the potential cancer cells develop or not, says Reeve. It seems to be dependent upon substances called prostaglandins which are formed from polyunsaturated fats in the body and if there is a deficiency in these prostaglandins the tumours won't grow.
Polyunsaturated fat, whether it's eaten in low concentrations or high concentrations, seems to be associated with a higher risk of getting skin cancer. The mice that didn't have any polyunsaturated fat, just totally saturated fat, in their diets were the ones that were protected. The equivalent in terms of human diet is a bit difficult because it is not possible for a person to avoid all polyunsaturated fats. It is not advisable either because there is a fatty acid deficiency disease that might afflict a person who did avoid all polyunsaturated fats. Reeve points out that we need polyunsaturated fat but if the intake is reduced it might also reduce the risk of skin cancer. Low levels of polyunsaturated fat caused less skin cancers in mice than did high levels.
They are now looking at alternative types of fats, for example fish oils. Fish oils contain an unusual type of super polyunsaturated fat which could replace the regular polyunsaturated fats in our diets. The prostaglandin equivalents which are produced from the fish oil type of polyunsaturates are different and have different biological activity. Evidence from other research would suggest that these different types would protect from rather than stimulate skin cancers, so they are looking at the possibility that the incorporation of fish oil into diet might have a protective function against skin cancer. They now have evidence that the fish oil diet protects from at lease one effect of UV exposure, the suppression of immunity.
There is a whole range of prostaglandins and for every prostaglandin with one particular type of biological activity there is a counterpart that has the anti-activity. The human body has a very sophisticated mechanism for balancing one prostaglandin's activity against another. Prostaglandins together seem to be a vast regulatory mechanism which control many functions.
The role of prostaglandins in the development of cancer is not fully understood by scientists. It is suspected that they might be involved in immune regulation and somehow be involved in the inability of the immune system to recognise tumour cells. Tumour cells are foreign cells and under normal conditions the immune system would recognise and kill those cells. But when a tumour grows successfully something has happened that has impaired the capacity of the immune system to recognise the tumour cells. Reeve thinks that the prostaglandins are involved in some way.
We suspect that the prostaglandin is involved because if we feed the mice a drug called indomethacin, which inhibits the formation of prostaglandins from the polyunsaturated fats, we get protection from skin cancer but we also get protection from the UV-induced impairment of immune function. So it would seem that there is a connection there somehow, she says.
Greenoak is also interested in the influences of diet on the effects of sunlight on skin, especially skin cancer. In collaboration with Associate Professor Ray Kierney of the Department of Infectious Diseases, Greenoak has tested the effects of controlled feeding on the susceptibility of the hairless mouse to skin cancer induced by the new solar simulator. Rather than restrict what the mice eat Greenoak has only restricted when the mice can eat and compared their susceptibility to mice who have eaten when they liked and had what he calls a grazing diet.
This grazing diet is common to all laboratory animals and also parallels the idea that it is better for humans to eat a little often. One group of mice were established on the grazing diet while another group have been allowed to eat only for six hours in each twenty four hour period. In six hours the mice eat as much as the companion group do in twenty four hours. The two groups of mice were then exposed to the same daily minimally reddening dose of simulated sunlight calculated to induce a 100% incidence of tumours in mice with the normal diet.
At 260 days from the start of the experiment and following ten weeks of daily exposure to sunlight, the normally fed mice which could eat when they liked had the expected 100% incidence of skin cancer and bore over 250 tumours on 15 mice. However, at the same time of observation the control fed mice had only 15% incidence and 10 tumours. Kierney had predicted this rather spectacular result entirely although Greenoak was sceptical.
Greenoak and Kierney met after a scientific meeting at which it seemed to Greenoak that only Kierney had offered a theory which made sense, and integrated all the conflicting data on skin cancer, immunology and dietary influences. In the absence of such a theory the scientific community tends to split up into camps of opinion each with their own irrefutable but also unreconcilable observations and data, says Greenoak. It is of course these tensions which can be very creative for the scientist who wants only to be aligned with sound theory and experimental practise. A desire which will often require courage when it means going against a powerfully political scientific orthodoxy.
Kierney had said that a daily period of fasting was not only a normal part of animal life but also of pre industrialised human societies. When food is wanted by an animal but is unavailable, endogenous corticosteroids are produced for the mobilisation of stored glycogen in the liver. These corticosteroids maintain a check on the inflammatory processes which will be activated as a consequence of any kind of tissue damage. According to Kierney it is the unchecked inflammatory processes which play a major role in the progress of a wide variety diseases in man, including cancer. Kierney refers to large body of literature much of it based on experiments over 20 years old which supports his thesis. But, he adds, all largely ignored.
Greenoak's experiment is the first to show the effect of controlled feeding in a spontaneous tumour system using sunlight as the carcinogen. The unequivocal result shows clearly that a simple, cost free, preventative measure for the reduction of skin cancer is also highly effective, at least in mice. The next phase of experimentation using controlled feeding is to see whether the same regime is effective at each stage of tumour initiation and development.
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