The prostate gland has a very complex architecture. It comprises glandular cells producing fluid of very intensely controlled composition (its components must be kept within extremely well-defined limits to be of maximum benefit for the sperm); ducts collecting the fluid; muscle cells that expel the fluid from the ducts: fibres that supply the ‘skeleton’ for the gland; nerves to co-ordinate the function of all these elements; and blood vessels to supply oxygen and nutrients.
None of these structures are static. The cells within them are constantly dying off and being renewed. They are continually exposed to hormones and ‘growth factors’ that stimulate their growth, and to the effects of genes that initiate their ‘suicide’ when they are too ‘old’ to function normally or are showing signs of becoming cancerous. It is when the balance between growth and death of cells is disturbed that prostate cancers start.
The foremost influence on prostate cell growth are male sex hormones. To the general public, the best known of these is testosterone. The word is in public use as a synonym for male strength and sexual potency. Testosterone itself is made in the testes and without it the prostate cannot develop. However, the testes are not the only source of male sex hormones. A small amount (much less than formed in the testes) is made by the adrenal glands, which lie over the upper surface of the kidneys. They produce two ‘androgens’ – hormones like testosterone that stimulate male sexual function – called androstene and androstenedione.
In normal circumstances, the effect of adrenal androgens on the prostate is tiny, as they are overwhelmed by the effects of testosterone. But if all testosterone is removed, such as by castration, or by drugs that block the effect of testosterone, then the adrenal androgens will still continue to stimulate prostate growth. This effect is vital when it comes to treating prostate cancer – it is sometimes necessary to remove the effect of adrenal, as well as testicular, male sex hormones from the prostate cancer cells.
It must be added here, for the sake of completeness, that the effects of testosterone and adrenal androgens on the prostate are not straightforward. To stimulate prostate cell growth they must first be converted, within the prostate, into dihydrotestosterone (DHT). This is done by a substance also produced in the prostate, called 5 alpha-reductase, or 5 alpha-R. If the action of 5 alpha-R can be blocked, then the prostate cells, normal or cancerous, lose the biggest stimulus to their growth. Without 5 alpha-R, the cell suicide pathway is unopposed. Within ten days of starting treatment to block 5 alpha-R. 90 per cent of the prostate cells are undergoing ‘suicide’.
This is why one of the first attacks on prostate cancer – or, for that matter, benign prostatic overgrowth or hypertrophy (BPH) – for many men is a drug to block 5 alpha-R. But it is not the only chink in the prostate cancer-cell armoury.
New genetic techniques have identified genes in the prostate that stimulate the cell suicide process. Genes are usually given a three-letter identity and sometimes a number, and convention dictates that they are printed in italics. The ‘good’ genes, as far as prostate cancer is concerned, in that they promote cancer cell suicide, are box and bcl-2. Another family of genes needed for control of normal cell growth is called Cdc2: they work along with a protein called cyclin to help prostate cells grow in an orderly, non-cancerous fashion.
These genes do this by forming substances called ‘growth factors’ (GFs). This is not the place to explain in detail how growth factors stimulate cells to grow and multiply. It is enough here to list the growth factors that have been identified in prostate tissue – they include epidermal GF, insulin-like GF, fibroblast GF, and transforming GF, among several others. Named mainly after the tissue or system that they stimulate, they are vital to understanding future treatments of prostate cancer. If the GF that stimulated the growth of a particular cancer can be identified, and its effects neutralized, or can be removed from the equation, then that cancer will stop growing. Research to achieve this aim is well on the path to success.
So how do prostate cancers start, and then continue? Knowledge of hormones, genes, and growth factors has given us many clues. Cancer of any tissue starts when a mutation, or several mutations, occur inside a cell that gives it an advantage in growth (or in resisting the message to commit suicide) over the cells surrounding it. No longer responding to the normal controls, it starts to produce -daughter” cells by dividing in two. (Cells divide in order to multiply, a curious anomaly for the mathematical mind.) As the numbers of its descendants increase, there is an increasing chance that one of them will undergo a further mutation, and the cancer will become less like the original normal cell. In medical terms, it becomes ‘de-differentiated’. This process eventually leads to the cells developing an ability to spread through the surface of the prostate to the surrounding tissues in the pelvis, and then, by-breaking into blood vessels, being carried in the circulation to distant sites in the body, where they can lodge and grow. This is called metastasis.
This series of cancer-inducing steps takes time, which is why most prostate cancers do not make themselves obvious until later middle age or old age. But it is common in the longer run: the experts predict that around 9 per cent of all men develop prostate cancer in their lifetimes. Thankfully, only a small minority of them, however, go on to die from their cancers.
Why do some men get them, and not others.’ For the answer we must go back to those genes. Some men possess “oncogenes’, genes that with a single mutation can alter the balance between growth and suicide in prostate cells. Many have already been identified. They include genes labelled as ra.v, sis, c-erb, c-myc, c-fos and c-jun. When these genes go wrong, they constantly give the cells the signal to grow and multiply and to ignore the suicide call. However, the body has its own way of protecting itself against oncogenes. It also possesses “anti-oncogenes’ or “tumour suppressor’ genes that oppose the activity of the oncogenes.
For example, one anti-oncogene was found by Professor David Lane and his team at Dundee University. Called p53, it stimulates cell suicide when it detects any abnormality inside the cell that may suggest a pre-cancerous change. If p53 is absent or bears a mutation that stops this vital function, the person has a highly increased risk of cancer, including prostate cancer. One research group found changes in the p53 gene in up to 80 per cent of prostate cancer specimens.
Stimulation of cell growth is only the first step. For the cancer to spread outside the prostate it needs also to be able to break through the surface, known as the “capsule”. For that to happen, other genetic mutations have to occur. The cancer cells have to lose the natural tendency of prostate cells to stick together inside the architecture of the organ. Cells normally stick together by means of “cell-adhesion’ molecules, called E-cadherin. The gene that forms E-cadherin is known to be sited on chromosome 16 (we have 23 pairs of chromosomes plus the sex chromosomes XX or XY). If that gene tails, then cells easily burst through the prostate capsule to spread within the pelvis.
Once outside the prostate, the cancer cells need to have a blood supply to stay alive. Amazingly, the researchers know how they form their own new source of blood. Cancer cells secrete substances (they are called angiogenesis factors) that stimulate the growth of new blood vessels around them, so that they can survive and grow elsewhere in the body. There is even an “antimetastatic factor’ identified on chromosome 17. produced by gene nni23. that acts against the angiogenesis factors. When that is lost, the cancer can spread beyond control.
All this new scientific information may seem frightening to anyone with prostate cancer or caring for someone with the disease. It is not meant to frighten, but to reassure – because the more we know about the mechanisms that cause cancer first to develop, then to spread within the pelvis, and finally to distant sites in the body, the better we are able to tight it. Already this knowledge has led to the development of drugs to block 5 alpha-R. They have had spectacular results in the clinic. Our knowledge of genes and chromosomes is leading to the identification of oncogenes, so that men at high risk can be watched to ensure that even the earliest change can be caught and dealt with as soon as it arises. New ways of identifying prostate cancer “markers”, substances that signal changes in chemistry before tumors are large enough to cause symptoms, have been developed. One marker, prostate specific antigen, is already being used routinely to identify cancers and to follow progress of treatment.
Although gene therapy is a few years away yet. there is progress towards ways of blocking oncogenes, renewing failed anti-oncogenes and tumour suppressor genes, and we are close to ways of improving people’s own immune system responses to prostate cancer.
We are already using androgen suppressor drugs to slow down and even arrest prostate cancers. We are drawing ever closer to finding medicines that will suppress the other growth factors that stimulate cancer cell growth, and to blocking angiogenesis. So there is optimism in the air among prostate cancer researchers and specialists.