Kidney Tumor Biomarkers Revealed by Simultaneous Multiple Matrix Metabolomics Analysis

Abstract

Metabolomics is increasingly being utilized in cancer biology for biomarker discovery and identification of potential novel therapeutic targets. However, a systematic metabolomics study of multiple biofluids to determine their interrelationships and to describe their utility as tumor proxies is lacking. Using a mouse xenograft model of kidney cancer, characterized by sub-capsular implantation of Caki-1 clear cell human kidney cancer cells, we examined tissue, serum, and urine all obtained simultaneously at baseline (urine) and at, or close to, animal sacrifice (tissue and plasma). Uniform metabolomics analysis of all three “matrices” was accomplished using GC- and LC-MS. Of all the metabolites identified (267 in tissue, 246 in serum, 267 in urine), 89 were detected in all 3 matrices, and the majority were altered in the same direction. Heat maps of individual metabolites showed that alterations in serum were more closely related to tissue than was urine. Two metabolites, cinnamoylglycine and nicotinamide, were concordantly and significantly (when corrected for multiple testing) altered in tissue and serum, and cysteine-glutathione disulfide showed the highest change (232.4-fold in tissue) of any metabolite. Based on these and other considerations, three pathways were chosen for biological validation of the metabolomic data, resulting in potential therapeutic target identification. These data show that serum metabolomics analysis is a more accurate proxy for tissue changes than urine, that tryptophan degradation (yielding anti-inflammatory metabolites) is highly represented in renal cell carcinoma, and support the concept that PPAR-alpha antagonism may be a potential therapeutic approach for this disease.

Global and Targeted Metabolomics of Esophageal Squamous Cell Carcinoma Discovers Potential Diagnostic and Therapeutic Biomarkers

“…Metabolomics, a growing field in systems biology (9 -11), has been shown to be a powerful approach to quantitatively measure global changes in the metabolic profiles of individuals in response to disease or treatment via noninvasive analyses of biofluids (12)(13)(14)(15)(16). Hence, metabolomics represents an excellent developing prospect for the discovery of diagnostic and therapeutic biomarkers.…”

The Nephrologist’s Tumor: Basic Biology and Management of Renal Cell Carcinoma

“…New therapeutic targets arise from metabolic reprogramming in RCC. Novel targets for therapeutic intervention on the basis of published work 10,85 are shown in bold. Kidney cancer cells exhibit increased glucose uptake, glycolysis, and lactate production, with an associated decrease in pyruvate entering the tricarboxylic acid (TCA) cycle.…”

Multivariate two-part statistics for analysis of correlated mass spectrometry data from multiple biological specimens

“…Equal masses of tissue samples were used in chromatographic analysis. Detailed information on the experimental procedures and metabolomic platforms were previously described in detail (Ganti et al, 2012). To illustrate our method, we retained 100 compounds detected in at least one sample in each biospecimen for analysis.…”

“…When omics data are obtained for multiple biospecimens from the same subject, analyses typically are conducted for each biospecimen separately and then results qualitatively compared across the biospecimens (Austdal et al, 2014;Ganti et al, 2012;Witowski et al, 2015;Yonezawa et al, 2013). However, multiple samples from the same subject are correlated and individually analyzing each biospecimen does not take advantage of this correlation.…”