The Biological basis of illness and therapeutics – Cancer of the prostate
Malignancies are currently responsible for more deaths in the UK than ischaemic heart disease (Cummings et al 1998). Half of these malignant deaths are from the “big four” – Lung, Bowel, Breast and Prostate (World Cancer Research Fund 1997). These cancers are almost unknown in developing countries but the incidence reverts to the UK norm within one or two generations of immigration, which argues strongly for the presence of environmental factors. If this is true then these malignancies should be theoretically preventable.
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Prostate cancer is the current most prevalent male cancer, accounting for about 30% of all new cases and also for about 14% of all malignant deaths (Montironi 2001). The incidence is increasing, this may, in part, be due to the increasing age of the male population. Increasing consumption of red meat and fats are associated with an increase in risk, and a diet of vegetables and salads (especially tomatoes) is associated with a lower risk. It appears that Vit E supplements significantly reduce the risk of developing the disease (Heinonen et al 1998)
Pathophysiology of the disease
The prostate is a walnut sized gland which is situated just below the male bladder. It is primarily responsible for producing the seminal fluid and it also produces some hormones.
In malignancy, there are several different forms. The neuroendocrine form (small cell type) can occur but it is not as common as the focal neuroendocrine type.
(Di Sant’Agnese 2000)
Prostate cancer is thought to arise primarily from one or more (usually a series) of genetic mutations in the DNA. This can either be inherited or acquired. (Hague et al 1996)
In the UK the majority of prostatic malignancies are thought to be mutations occurring at directly at the tumour site rather than being genetically inherited.(Bingham et al 1998)
The genetic mechanisms can involve either the activation of an oncogene or the inhibition of a tumour supressor gene. The mechanism is not simple, and it is thought that about four to six stepwise mutations in the DNA are responsible for the genesis of prostate cancer.
The actual mechanism of the acquired genetic mutation is thought to be when an oncogene is translocated and fused with the activity promoter of another gene, this mechanism is often found when specific tumour markers are detected in the blood (viz. PSA). A similar mechanism is implicated in the more aggressive forms of prostatic cancer where the oncogene combines (and thereby inhibits) a tumour supressor gene. Demonstration of abnormal amounts of proteins such as PSA are useful in detecting the presence of micro-metastases when the disease process is thought to be in remission.
The original sequence of the DNA is thereby changed. The actual mechanism can be by translocation (as described above) or by insertions or inversions which are more usually due to errors of RNA translation. All of these mechanisms ultimately exert their effect by interfering with the proper regulatory controls of the protein manufacturing abilities of the cell
One of the main pathological features of malignancy is the neovascularisation that almost universally occurs. It is thought to begin in Benign Prostatatic Hypertrophy (BPH), and progresses through the pre-malignant into the frank malignant state. (Bostwick et al 2000)
This is thought to be a result of the increase in detectable levels of Vascular Endothelial Growth Factor (VEGF). The levels of VEGF are highest in the most malignant forms of the disease, and is amenable to external hormonal manipulation. The commonest sites of metastatic disease are in the bone and the liver. (Mazzucchelli et al 2000)
There is considerable evidence to support the implication of oncogenes in the aetiology of this cancer. Oncogenes such as c-myc and c-erb-B of have been found, as have supressor genes such as p27(Kip1) and pp32R1/2. Oncogenes have also been implicated in the formation and regression of the metastatic form of the disease. (Lijovic et al 2000)
There appears to be a genetic association with the cancer as 10% of sufferers have a family history of the disease (Selley et al 1997)
Modern management of prostate cancer
The management of prostate cancer is primarily dependent on the clinical staging. There are several different types of staging currently employed. The commonest is the Gleason staging (I-IV) with III being the clinically commonest presentation.
Significant factors in the staging are:
- Neuroendocrine differentiation
- Perineural invasion
- Proliferation markers
Other factors also play a part including the PSA and other blood borne entities. The first two factors are arguably the most important.
We have learned a great deal about the detection and treatment of prostate cancer in the recent past, but the mortality figures do not reflect the increase in our knowledge. The two overriding clinical factors are early detection (ideally in the pre-invasive state) and the identification of the other prognostic factors.
Chemoprevention is a field that is gaining in momentum at the present, but it is still largely experimental. (Montironi et al 1999)
The current mainstay of treatment at present is hormonal manipulation
A recent paper by Armstrong (et al 2001) looks at the current role of cellular immunotherapy in the field of prostate cancer management. This is a field which also holds exciting practical prospects for tumour management. It involves giving the patient vaccines prepared from antigenically active tumour cells or activated lymphocytes. Specifically cytotoxic T-lymphocytes are used to identify and then destroy the tumour cells. They do this by being programmed to recognise a specific protein on the surface of the malignant prostate cell.
Clinical trials have shown that this method of treatment is at its most effective when first line (hormonal) treatment has reduced the size of the tumour to a residual amount, which is at high risk of relapse. For reasons that are not yet fully understood, this method appears to suffer from a developing tolerance to the malignancy by the lymphocytes. This is currently the focus of intense research activity. ( Hwu et al.1999)
A more recent development still is an offshoot of this type of treatment and that is the use of gene modified vaccines. This involves vaccines which contain genetically modified cells. The most effective found so far are those which work by making cells increase the production of cytokines in close proximity to the tumour cells.
(Alvarez-Vallina et al 1996)
This appears to increase the antigenic appeal of those cells and thereby render them more amenable to attack from the immune system. This avoids the difficulties with the side effects that were seen when cytokines were given systemically. (Gao et al 2000)
Other mechanisms for gene therapy involve the ingenious use of viruses to transfer the altered DNA into the malignant cell. In prostate malignancies, their use has been disappointing because of problems with side effects, but the theory is also promising (Relph et al 2004)
PSA and related proteins such as prostate specific membrane antigen (PSMA) are commonly helpful in monitoring the progress or relapse of the disease
PSA is being experimentally exploited by being coupled to enzymes such as thymidine kinease. This can be placed in the body by a retrovirus and therefore infects all cells but is only activated in prostate cells. They are refered to as the Trojan Horse Vectors and appear to very successful in early trials. Proponents of the technique refer to it as performing a genetic prostatectomy.
More modern techniques still involves the detection of prostate cells in the bloodstream using a reverse transcriptase and polymerase chain reaction. This is thought to be a particularly sensitive assay for the prediction of surgical failure (Olsson et al 2003)
The downside to these treatments involving genes, is that the mechanisms of protein synthesis and regulation are unimaginably complex. Attempts to cure one malignancy may unwittingly cause another by a process called Insertional mutagenesis, where the desired effect in one cell is hindered by an unwanted malignant change in another. (Armstrong 2001)
The advances in our understanding of the molecular basis of prostate cancer have been spectacular in the last decade. Interventional genetics now are on the brink of offering a real chance of survival to patients with resistant disease. Patients with widespread disease are usually desperate to try any form of novel treatment. Although the theory and understanding of many of the oncogenic processes are already well advanced, it is vital not to give a patient false hope of cure. (Bingham et al 1998)
To this end the Dept. of Health has set up a new governing body in the shape of he Genetic Therapy Advisory Committee (GTAC) to consider and oversee all new and proposed treatments.
The major hurdles that remain in this field are how to effect the stable and specific transfer of genes into tumour cells, how to ensure the safety of both patients and staff and to define exactly where the best place is for gene therapy alongside the mainstream treatments today. (Montironi 2001)
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