Monday November 15 2010
The causes of prostate cancer are not known
“Prostate cancer treatments are likely to dramatically improve after scientists discovered what causes the condition,” reported the Daily Mail. The newspaper said that a study has found androgens (male hormones) “promote the fusion of two specific genes which fuel the growth of cancer”.
This research found that long-term exposure to androgen increases the likelihood of genetic changes in prostate cells in the laboratory. If similar changes occur in the body, they could contribute to the formation of cancers.
Importantly, this study has not identified what causes all prostate cancers, but it has identified that testosterone might play a role. The exact causes of prostate cancer are not known, and various factors are likely to be involved. Known risk factors include age, ethnic group and family history.
Further studies will be needed to conclusively determine whether high androgen levels are a risk factor for the disease.
Where did the story come from?
The study was carried out by researchers from Queen Mary University of London. Funding was provided by the male cancer charity Orchid and the UK Medical Research Council.
The study was published in the peer-reviewed medical journal Cancer Research.
The Daily Mail, Daily Mirror and Guardian covered this study. The Mail reported that “prostate cancer treatments are likely to dramatically improve after scientists discovered what causes the condition”. However, this study only found that male hormones can increase the likelihood of genetic changes in prostate cells in the laboratory. These genetic changes could contribute to the formation of prostate cancers but does not mean that the cause of all prostate cancers has been discovered.
What kind of research was this?
This laboratory study investigated the effects of the male hormone androgen on one type of genetic abnormality. Genes that are not normally joined to each other can fuse if chromosomes break and rejoin in an abnormal way. Genes formed in this way are called ‘fusion genes’, and they can lead to uncontrolled cell division and contribute to tumour formation and progression depending on the genes involved. For example, in about half of all prostate cancers, the TMPRSS2 gene fuses with the ERG gene.
The researchers say it is not clear what causes these gene fusions however. One theory, they say, is that proteins that are involved in regulating the activity of genes (called transcription factors) could bring together genes that are not normally close, and this could potentially be a time when gene fusion could occur. As the male hormone androgen is involved in regulating the activity of the TMPRSS2 gene, the researchers thought it was possible that it could promote the formation of TMPRSS2:ERG fusion genes.
This type of research helps researchers to understand the events that occur in cells which lead to them becoming cancerous. In the future, this knowledge may help suggest factors that influence the development of prostate cancer, or ways to treat or prevent cancers, but it is a early step towards this goal.
What did the research involve?
The experiments used both malignant and non-malignant prostate cells that had been grown in the laboratory. The laboratory-grown prostate cells were treated with the androgen dihydrotestosterone (DHT) for either three hours, or with high doses of DHT on an ongoing basis. The cells were then tested to see whether they contained active TMPRSS2:ERG fusion genes.
The researchers also examined how DHT treatment affected factors that might influence the formation of fusion genes. This included using fluorescent probes to look at whether the TMPRSS2 and ERG genes were in close proximity. This is because the proximity of the genes to each other may influence the likelihood of them breaking and fusing. They also measured the activity of a gene called PIWIL1, which is thought to protect cells from genetic rearrangements by stopping the DNA in chromosomes from breaking.
The researchers also looked at prostate cancer samples taken from 40 patients. They investigated whether men with particular genetic variations associated with more active androgen receptors are more likely to carry fusion genes in their prostate cancers.
What were the basic results?
The researchers found that treating both malignant and non-malignant prostate cells with androgen leads to the formation of TMPRSS2:ERG fusion genes. Malignant prostate cells were more susceptible and produced active the fusion genes within 24 hours of being treated. Non-malignant prostate cells had no active TMPRSS2:ERG fusion genes when tested after 24 hours. However, the active fusion genes were detected in non-malignant prostate cells that had been treated with androgen for five months. The fusion gene was not detected in untreated cells. Higher doses of androgen were more likely to induce the formation of fusion genes.
In the next part of their experiment, the researchers used fluorescent probes to look at whether androgen treatment brought the TMPRSS2 and ERG genes closer together. They found that in prostate cells treated with DHT for three hours, the TMPRSS2 and ERG genes were more likely to be close together in the nucleus than in untreated cells. This occurred less in malignant than non-malignant cells. This suggested there are factors other than spatial proximity of the genes that also influence the likelihood of the genes fusing.
The researchers found that the long-term treatment of prostate cells with androgen reduced the activity of the PIWIL1 gene, which is thought to protect cells from genetic rearrangements by stopping the DNA in chromosomes from breaking. The PIWIL1 gene was also less active in malignant prostate cancer cells than non-malignant prostate cells.
Men with TMPRSS2:ERG fusion genes in their prostate cancer tissue tended to have more active androgen receptors, but this link was not strong enough to be statistically significant.
How did the researchers interpret the results?
The researchers conclude that long-term androgen treatment can lead to fusion gene formation in non-malignant prostate cells. They suggest that the formation of this fusion gene is an early event in the formation of prostate cancer.
This study found that long-term androgen treatment of prostate cancer cells in the laboratory can increase the likelihood of the formation of a particular fusion gene called TMPRSS2:ERG. This type of study helps researchers to understand the events that occur in a cell on the way to becoming cancerous.
The causes of prostate cancer are not known, and various factors are likely to play a role. Known risk factors include age, ethnic group and family history, with prostate cancer being more common in older men, men of Afro-Caribbean and African descent, and men with a family history of the disease.
Importantly, this study has not identified what causes all prostate cancers but it has identified one factor that might play a role: testosterone. A different type of study is needed to determine whether men with higher levels of testosterone are more or less likely to develop prostate cancer. This would ideally be a prospective cohort study, measuring men’s testosterone levels and following them over time to see who developed the disease.