Presence of TMPRSS2-ERG is associated with alterations of the metabolic profile in human prostate cancer

Abstract

TMPRSS2-ERG has been proposed to be a prognostic marker for prostate cancer. The aim of this study was to identify changes in metabolism, genes and biochemical recurrence related to TMPRSS2-ERG by using an integrated approach, combining metabolomics, transcriptomics, histopathology and clinical data in a cohort of 129 human prostate samples (41 patients). Metabolic analyses revealed lower concentrations of citrate and spermine comparing ERGhigh to ERGlow samples, suggesting an increased cancer aggressiveness of ERGhigh compared to ERGlow. These results could be validated in a separate cohort, consisting of 40 samples (40 patients), and magnetic resonance spectroscopy imaging (MRSI) indicated an in vivo translational potential. Alterations of gene expression levels associated with key enzymes in the metabolism of citrate and polyamines were in consistence with the metabolic results. Furthermore, the metabolic alterations between ERGhigh and ERGlow were more pronounced in low Gleason samples than in high Gleason samples, suggesting it as a potential tool for risk stratification. However, no significant difference in biochemical recurrence was detected, although a trend towards significance was detected for low Gleason samples. Using an integrated approach, this study suggests TMPRSS2-ERG as a potential risk stratification tool for inclusion of active surveillance patients.

Multiple markers for the non-invasive diagnosis and characterisation of prostate cancer

“…Thus, a sample collection/storage protocol should be implemented that limits the PAP reaction to 2-3% progression, such as our recommendation that ejaculate samples be collected in a sterile urine jar containing 5 mM tartrate in 20 ml PBS solution cooled to 277 K 354 . While malignant prostatic metabolite contribution to ejaculate, considering concurrent contributions from multiple organs and resulting proteolysis, may intuitively be minimal or diluted, our findings are like those seen in tissue extracts and in vivo 279,280 , likely to be enhanced by spectral acquisition at 900 MHz.…”

“…Indeed, Hansen and colleagues corroborated in vitro 1 H HR-MAS NMR findings with in vivo 1 H MRSI, suggesting that MRSI may provide an avenue to stratify patients prior to biopsy or monitor metabolite profiles in vivo in active surveillance programs, potentially in place of repeat biopsy 279 . Furthermore, metabolite profile changes due to ADT could be monitored using 1 H MRSI, shown in vitro using 1 H HR-MAS NMR 24 .…”

“…Reduced spermidine may be due to increased spermidine synthase and spermidine N(1)-acetyltransferase 279 , while elevated spermidine and glutathione has been observed in CaP samples 280 .…”

“…Aspartate, isoleucine, tyrosine and tryptophan were correlated with ERG status, while reduced maltotriose and gluconic acid were seen in ERG positive samples 280 , a relationship also reported for earlier biochemical recurrence 281 . Gene enrichment meta-analysis considering metabolic pathways related to ERG status demonstrated glutathione, polyamine and glycolysis as well as purine and pyrimidine metabolism to be deranged, which was more pronounced in lower Gleason grade tumours 279 . These important studies linked well-described and clinically used genetic changes to metabolic aberrations to improve understanding of metabolic pathways in early CaP development and potentially demonstrate the initiation of tumorigenesis.…”

“…Specifically, reduced cellular citrate levels are due to reduced aconitase 2 expression coupled with increased expression of lipogenic enzymes (acetyl-CoA carboxylase alpha and fatty acid synthase) 279,280 . These expression patterns suggest citrate mobilisation to the cytosol for de novo fatty acid synthesis, which may indicate an aggressive phenotype, given association with tumour progression and reduced survival 282 .…”