Metabolomics: a novel approach to early and noninvasive prostate cancer detection

Abstract

Prostate cancer (PCa) is the most commonly diagnosed visceral cancer in men and is responsible for the second highest cancer-related male mortality rate in Western countries, with increasing rates being reported in Korea, Japan, and China. Considering the low sensitivity of prostate-specific antigen (PSA) testing, it is widely agreed that reliable, age-independent markers of the presence, nature, and progression of PCa are required to facilitate diagnosis and timely treatment. Metabolomics or metabonomics has recently emerged as a novel method of PCa detection owing to its ability to monitor changes in the metabolic signature, within biofluids or tissue, that reflect changes in phenotype and function. This review outlines the physiology of prostate tissue and prostatic fluid in health and in malignancy in relation to metabolomics as well as the principles underlying the methods of metabolomic quantification. Promising metabolites, metabolic profiles, and their correlation with the presence and stage of PCa are summarized. Application of metabolomics to biofluids and in vivo quantification as well as the direction of current research in supplementing and improving current methods of detection are discussed. The current debate in the urology literature on sarcosine as a potential biomarker for PCa is reviewed and discussed. Metabolomics promises to be a valuable tool in the early detection of PCa that may enable earlier treatment and improved clinical outcomes.

Keywords: Biological markers; Detection; Metabolomics; Prostatic neoplasms.

FIG. 1

Summary of targets in the 'omic' era of analysis. The hierarchical levels of cellular organization involved in the progression from genotype to phenotype are shown. This expression of cellular phenotype is tightly regulated by feedback mechanisms, as shown above the progression. Through this process, various targets are available for analysis and opportunistic manipulation, as shown below the progression.

FIG. 2

Summary of peripheral prostate physiology in health (left) and disease (right). Healthy peripheral prostate physiology involves citrate accumulation via the zinc-dependent inhibition of m-aconitase, resulting in reduced ATP production via the Krebs cycle and a greater dependence on glucose and aspartate for ATP. In malignancy, peripheral prostate cells lose their ability to accumulate zinc, resulting in isomerization of citrate via m-aconitase for metabolism in the Krebs cycle and reduced citrate accumulation and production.

FIG. 3

Relationships between different quantification methods. The relationships between different quantification methods are shown. The basic techniques of quantification are listed on the left side, their relationships and combinations are shown in the middle of the diagram, and the result of these relationships is shown on the right side. These are the principal methods of quantification in prostate cancer (PCa) metabolomics. LC-MS: liquid chromatography mass spectrometry, GC-MS: gas chromatography mass spectrometry, NMR: nuclear magnetic resonance, MRI: magnetic resonance imaging, MRSI: magnetic resonance spectroscopic imaging, PET: positron emission tomography.