US scientists have found that a molecule called sarcosine, a byproduct of metabolism that is eliminated via urine, could be an effective marker for prostate cancer and that simple urine tests that measure concentrations of this marker might one day reduce the need for invasive biopsies.

The research behind the discovery is written up as an article in the 12 February issue of Nature, and was the work of Dr Christopher Beecher at the University of Michigan in Ann Arbor, and a large team of colleagues, including researchers from other centers in the US.

For this study, the researchers inspected metabolites (byproducts of natural chemical reactions in the body) in 262 samples from prostate cancer patients who were at various stages of the disease, so that samples ranged from containing benign cells to aggressive metastized tumors that had already spread to other organs. As cancers progress from early to late stages, the concentration of metabolites associated with these changes vary.

Scientists already have a list of “likely suspects” for metabolic byproducts that could indicate changes in prostate cancer progression, but what is special about this study is that Beecher and colleagues decided to widen their search to include all the metabolites present in the samples they had, including some that were not considered “likely suspects”. They were able to do this because they used mass spectrometry, which picks up all the molecules in a sample and presents a unique signature for each one.

And, as often happens in science, the result was a complete surprise, because the best contender was not among the “likely suspects”.

As Beecher explained to Nature News:

“We would never have expected to see sarcosine, nor would we have expected to look for it.”

Sarcosine is a byproduct of the amino acid glycine. Beecher and colleagues actually found at least 6 metabolites that were present in higher concentrations in the more advanced metastatic cancer samples compared to samples of earlier stages of the disease, but sarcosine was by far the highest.

The researchers went on to identify the enzymes that make and break down sarcosine and altered the genes that control these processes in lab cultured cells.

As Beecher explained, any time the researchers did anything that increased the production of sarcosine, the cells “started to move so much they could get themselves into a sample of gelatine under their own force”, a characteristic behaviour of cancerous cells. The researchers found that just adding sarcosine to benign prostate cells made them act like cancerous cells.

This suggests that sarcosine is not only a marker of how aggressive a cancer is, but it is also active in making cells cancerous.

The researchers said their findings could offer targets for new treatments, as Malcolm Mason, a prostate cancer expert from Cardiff University in Wales, UK, who also works for Cancer Research UK, explained, there is enough evidence here to warrant looking at using sarcosine as a new drug target:

“Not only have they got a marker that has a fundamental role in invasion and metastasis, the molecule itself is regulated by systems that have been directly implicated in prostate cancer.”

However, Mason emphasized that the findings need to be confirmed by other studies, and he also cautioned that sarcosine is unlikely to be used widely in screening programs; there are several studies under way in Europe looking at possible new markers already. Mason said urine tests for sarcosine would not be like tests you can do in the pharmacy: they will most likely be used to help specialists decide if and when to do biopsies.

However, Beecher is hopeful that sarcosine will play a bigger role and tests based on it will one day replace current tests.

“This may actually be superior to PSA,” he said. The researchers suggested that there could one day be a test for a “panel of metabolites”.

Beecher and colleagues are planning to use their research method to look at metabolites of other diseases.

Present ways of screening for prostate cancer rely primarily on testing concentrations of prostate specific antigen (PSA) in the blood. PSA is a protein that binds to prostate cancer cells. The free PSA test is another guide: it checks how much of the PSA has not bound to cancer cells, and the theory is that the more free PSA there is the less cancer there is, but as many specialists know, it is not an exact science, and biopsy is still the definitive way of checking whether the cancer is there and if so how aggressive it is.

There is also another test called the PCA3 test that looks for a particular protein in the urine; PCA3 is a protein that is only released by prostate cancer cells. However, according to Cancer Research UK, the test is still new and there is not enough information about how reliable it is, although the company that markets the test says it is. So in reality, the prostate cancer specialist does not rely solely on markers for a firm diagnosis, but may well use them to decide whether to proceed with a biopsy now or later.

Having another marker, as suggested by this study, is likely to help them make that decision with more confidence, but as Mason suggests, perhaps delaying biopsy rather than avoiding it altogether. Either way it gives them another view on how to assess the status of any potential prostate cancer.

Figures from Cancer Research UK suggest that more than 670,000 men worldwide discover they have prostate cancer every year. Survival varies depending on screening and treatment methods, but in the UK it is estimated that about 30 per cent of men die within 5 years of being diagnosed with the disease.

“Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression.”
. Arun Sreekumar, Laila M. Poisson, Thekkelnaycke M. Rajendiran, Amjad P. Khan, Qi Cao, Jindan Yu, Bharathi Laxman, Rohit Mehra, Robert J. Lonigro, Yong Li, Mukesh K. Nyati, Aarif Ahsan, Shanker Kalyana-Sundaram, Bo Han, Xuhong Cao, Jaeman Byun, Gilbert S. Omenn, Debashis Ghosh, Subramaniam Pennathur, Danny C. Alexander, Alvin Berger, Jeffrey R. Shuster, John T. Wei, Sooryanarayana Varambally, Christopher Beecher, Arul M. Chinnaiyan.
Nature 457, pp 910 – 914 (12 Feb 2009).
doi: 10.1038/nature07762

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Sources: Nature News.

Written by: Catharine Paddock, PhD