Prostate news article, January 2006
BREAKING THE MOLECULAR CODE FOR PROSTATE CANCER Dr Mark R Feneley Senior Lecturer in Urological Oncology |
Research, supported by Prostate Research Campaign UK at the Prostate Cancer Research Centre (PCRC) has been characterising molecular changes in early stage prostate cancer and relating these changes to the ability acquired by prostate cancer to invade and metastasise.
Patients and their doctors faced with the diagnosis of prostate cancer are always anxious to know when treatment will be curative - that means to say, whether or not the cancer will return again after any given treatment. Scans showing no sign of spread beyond the prostate may offer some reassurance, but even pathological stage, the single most valuable predictor of recurrence after radical prostatectomy offers no guarantee. For most men with organ-confined prostate cancer, the immediate risk to their health is low, and in the PSA era few of these patients relapse following definitive treatment. For individuals with non-organ confined disease, recurrence-free survival is more difficult to assure; for some, treatment will be curative, but for others, it may be too late.
The fundamental scientific question, still unanswered, addresses the molecular differences that determine the ability of early stage disease to metastasise. Traditional assessment, evaluating microscopic extension of cancer beyond the prostate and the architectural appearances of the tumour, are neither sufficiently discriminatory nor prognostically reliable for individual patients. Consequently, increasing attention is being directed to the progressive cellular deregulation acquired by a developing cancer.
To understanding cancer behaviour, it is fundamental to appreciate that a tumour’s ability to spread (metastasise) is not inherent within cancerous cells when they first develop. This capacity is acquired. Cancer represents a disease of cellular sequential genomic derangement, and it originates from abnormal progeny of normal cells, though stepwise genetic mutations. A single mutation however is insufficient to transform a normal cell into a malignant cell. Cancer represents the consequences of a progression of genetic aberrations acquired through successive cell divisions, providing progeny cancer cells with survival advantages over normal cells.
At the PCRC, University College London, the malignant behaviour of prostate cancer is being related to genetic changes acquired in the very early stages of development. From a database of patients who have had radical prostatectomy, 84 surgical specimens have been identified to investigate and characterise the molecular abnormalities that distinguish cancers that have recurred within two years from those that did not. The 42 patient pairs are matched for tumour characteristics (stage and grade), and preoperative PSA. Using the matched pairs, comparing samples from patients with and without biochemical progression, cellular molecules, genes and chromosomal structure growth regulators can be examined in prostate cancer tissue.
A tissue microarray has been constructed and used to assess simultaneously a large number of molecular markers (biomarkers) under the same standardised conditions. A tissue microarray comprises multiple samples of tissue cores (taken from the radical prostatectomy specimens) embedded in a block of paraffin. The PCRC program has examined several biomarkers, including those called BCL-2, p53, Ki67 and E-cadherin. These are involved in cellular processes that specifically regulate programmed cell death (bcl-2, p53) - (a normal cell’s response to genetic damage), cellular proliferation (Ki-67) and cellular adhesion (E-cadherin). Recent results indicate that there is an inconsistent relationship between some of these candidate biomarkers and the behaviour of prostate cancer. The effect of abnormal biomarker expression therefore requires further investigation, particularly their relation to other molecular and genomic changes and the pattern of disease behaviour.
Another technique called Array Comparative Genomic Hybridisation is being used to examine genetic changes associated with cancer. Using this technique, various chromosomal changes associated with prostate cancer have been identified in cell cultures. The 23 pairs of chromosomes contain the entire genetic code for all human cell’s molecular processes. Changes include a gain of chromosome 7, deletion of chromosome 8, both gains and losses of chromosome 11, loss of 18p and gain of 20q. Specific gene defects can be mapped to chromosomal rearrangements, revealing further candidate gene mutations for investigation. These results have been published in Prostate Cancer and Prostatic Diseases, (Brookman-Amissah et al 2005). This same technique is being used in the radical prostatectomy specimens, to relate changes in the cell genome to cancer behaviour after radical prostatectomy.
The aim of ongoing research projects at PCRC is to determine the molecular signatures that distinguish tumours that can be cured by definitive treatment, from those that will relapse. If these signatures can be identified in prostate samples before treatment, this will be a powerful instrument to guide therapeutic decisions. Molecular research is of great importance if the complex and often interrelated changes in the cell’s molecular hierarchy are to be unravelled and understood. Just as present generations take for granted benefits derived from historical discovery, future generations depend upon current support and investment in medical research for their chances of better diagnosis and treatment.
Brookman-Amissah N, Duchesnes C, Williamson MP, Wang Q, Ahmed A, Feneley MR, Mackay A, Freeman A, Fenwick K, Iravani M, Weber B, Ashworth A, Masters JR. Genome-wide screening for genetic changes in a matched pair of benign and prostate cancer cell lines using array CGH. Prostate Cancer Prostatic Dis. 2005; 8(4): 335-43.
Acknowledgements
The research discussed in the article above is funded by grants from Prostate
Research Campaign UK to Mr Mark Feneley, Dr Alex Freeman, Mr Simon
Bott and Dr Magali Williamson, at the Prostate Cancer Research Centre,
University College London. The contributions of Professor John
Masters, Mr Joe Nariculam, Dr Cecile Duchesnes and Dr Nicola Brookman-Amissah
as members of this research team are also gratefully acknowledged.