Multiple, complex molecular events characterize
cancer development and progression. Deciphering the molecular networks that distinguish organ-confined disease from metastatic disease may lead to the identification of critical
biomarkers for
cancer invasion and disease aggressiveness. Although gene and
protein expression have been extensively profiled in human tumours, little is known about the global metabolomic alterations that characterize neoplastic progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we profiled more than 1,126 metabolites across 262 clinical samples related to
prostate cancer (42 tissues and 110 each of urine and plasma). These unbiased metabolomic profiles were able to distinguish benign prostate, clinically localized
prostate cancer and metastatic disease.
Sarcosine, an N-methyl derivative of the
amino acid glycine, was identified as a differential metabolite that was highly increased during
prostate cancer progression to
metastasis and can be detected non-invasively in urine.
Sarcosine levels were also increased in invasive
prostate cancer cell lines relative to benign prostate epithelial cells. Knockdown of
glycine-N-methyl transferase, the
enzyme that generates
sarcosine from
glycine, attenuated
prostate cancer invasion. Addition of exogenous
sarcosine or knockdown of the
enzyme that leads to
sarcosine degradation,
sarcosine dehydrogenase, induced an invasive phenotype in benign prostate epithelial cells.
Androgen receptor and the ERG gene fusion product coordinately regulate components of the
sarcosine pathway. Here, by profiling the metabolomic alterations of
prostate cancer progression, we reveal
sarcosine as a potentially important metabolic intermediary of
cancer cell invasion and aggressivity.