| DETERMINATION
OF THE STEM CELL GENE EXPRESSION PROFILE OF NORMAL PROSTATE,
BPH AND CARCINOMA OF THE PROSTATE.
Benjamin Grey University of Manchester, Paterson Institute for Cancer Research. Christie Hospital, Manchester |
 |
Prostate-Benign Prostatic Hyperplasia (BPH) affects approximately half the male population over the age of 50 years and is an important cause of morbidity. The treatment of problems arising as a consequence presents a major public health burden, accounting for a significant proportion of a Urology department's workload and major input from primary and secondary health care. The objective of currently available therapy is to treat the problems arising consequent to bladder outflow obstruction.
Symptoms attributable to BPH are an important cause of morbidity and can significantly affect the patient's quality of life. Treatment is available in the form of medication or surgery. However, such treatments deal with the consequences of BPH rather than the root cause. Therapies are not without potential side effects, which may in turn be more troublesome for the patient than the original symptoms.
Carcinoma of the prostate (CaP) is now the commonest male cancer diagnosed and has become the second commonest cause of cancer-related death in men. In the UK there are over 34,900 new cases each year resulting in 10,000 deaths annually. CaP presents the medical profession with several challenges. The natural history of CaP is unclear and often difficult to predict for an individual patient. In turn this can lead to difficulty in determining which patients require radical treatment and which may be safely observed. Patients with locally advanced or metastatic spread of the disease at presentation are not amenable to curative treatment and their disease is controlled initially by anti-androgen therapies. Those patients who subsequently develop hormone-refractory disease (HRPC) have an average life expectancy of 18 months.
Prostate stem cells are believed to be responsible for the control of normal growth and repair of damage within the prostate. Mutations of the genes responsible for controlling these key processes are believed to be the cause of the uncontrolled proliferation of cells that subsequently causes the enlargement of the prostate and symptoms that are seen in BPH. Isolation of stem cells for further study has proven very difficult as they are rare and, as yet, there have been no biological markers identified that are helpful in selecting for that specific cell type. However, we have developed a technique called the Hoechst dye efflux assay which identifies a population of cells (the side population) which can then be collected separately from the rest of the prostate sample.
Aims:
1. To use Affymetrix microarray on small side population cell numbers
to determine the differential gene expression profile for the CD45-ve
/ CD133-ve Hoechst 33342lo side population versus the CD133+ve Hoechstlo
side population.
2. To elucidate novel markers for the identification and isolation of
prostate stem cells.
3. To determine the molecular pathways specific to stem cell homeostasis
and the changes that confer a phenotype consistent with BPH and CaP.
Identification of such pathways would then allow better understanding
of the causes of prostate stem cell dysfunction.
4. To utilise genetic markers and pathways to develop diagnostic and
prognostic profiles and elucidate novel targeted therapies against the
root cause of both benign and malignant disease.
Research summary, 25 March 2008.
Project 2007/12