Integration of tissue metabolomics, transcriptomics and immunohistochemistry revealsERG-and gleason score-specific metabolomic alterations in prostate cancer

Abstract

Integrated analysis of metabolomics, transcriptomics and immunohistochemistry can contribute to a deeper understanding of biological processes altered in cancer and possibly enable improved diagnostic or prognostic tests. In this study, a set of 254 metabolites was determined by gas-chromatography/liquid chromatography-mass spectrometry in matched malignant and non-malignant prostatectomy samples of 106 prostate cancer (PCa) patients. Transcription analysis of matched samples was performed on a set of 15 PCa patients using Affymetrix U133 Plus 2.0 arrays. Expression of several proteins was immunohistochemically determined in 41 matched patient samples and the association with clinico-pathological parameters was analyzed by an integrated data analysis. These results further outline the highly deregulated metabolism of fatty acids, sphingolipids and polyamines in PCa. For the first time, the impact of the ERG translocation on the metabolome was demonstrated, highlighting an altered fatty acid oxidation in TMPRSS2-ERG translocation positive PCa specimens. Furthermore, alterations in cholesterol metabolism were found preferentially in high grade tumors, enabling the cells to create energy storage. With this integrated analysis we could not only confirm several findings from previous metabolomic studies, but also contradict others and finally expand our concepts of deregulated biological pathways in PCa.

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

“…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 .…”

“…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 .…”

“…A recent key advancement has shown metabolic aberrations to be most pronounced in early malignant transformation, a notion hypothesised for some time 20 cholesterol metabolism, potentially improving energy storage 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 .…”

“…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 .…”

“…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 . Concomitantly elevated ATP citrate lyase may also implicate carbohydrate metabolism in malignant transformation 280 . Reduced cellular spermine in…”