Pancreatic ductal adenocarcinoma is associated with a distinct urinary metabolomic signature.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis in part due to the lack of early detection and screening methods. Metabolomics provides a means for noninvasive screening of tumor-associated perturbations in cellular metabolism. METHODS: Urine samples of PDAC patients (n = 32), healthy age and gender-matched controls (n = 32), and patients with benign pancreatic conditions (n = 25) were examined using (1)H-NMR spectroscopy. Targeted profiling of spectra permitted quantification of 66 metabolites. Unsupervised (principal component analysis, PCA) and supervised (orthogonal partial-least squares discriminant analysis, OPLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra using SIMCA-P(+) (version 12, Umetrics, Sweden). RESULTS: Clear distinction between PDAC and controls was noted when using OPLS-DA. Significant differences in metabolite concentrations between cancers and controls (p < 0.001) were noted. Model parameters for both goodness of fit, and predictive capability were high (R (2) = 0.85; Q (2) = 0.59, respectively). Internal validation methods were used to confirm model validity. Sensitivity and specificity of the multivariate OPLS-DA model were summarized using a receiver operating characteristics (ROC) curve, with an area under the curve (AUROC) = 0.988, indicating strong predictive power. Preliminary analysis revealed an AUROC = 0.958 for the model of benign pancreatic disease compared with PDAC, and suggest that the cancer-associated metabolomic signature dissipates following RO resection. CONCLUSIONS: Urinary metabolomics detected distinct differences in the metabolic profiles of pancreatic cancer compared with healthy controls and benign pancreatic disease. These preliminary results suggest that metabolomic approaches may facilitate discovery of novel pancreatic cancer biomarkers.

Urinary metabolomic signature of esophageal cancer and Barrett's esophagus.

BACKGROUND: Esophageal adenocarcinoma (EAC) often presents at a late, incurable stage, and mortality has increased substantially, due to an increase in incidence of EAC arising out of Barrett's esophagus. When diagnosed early, however, the combination of surgery and adjuvant therapies is associated with high cure rates. Metabolomics provides a means for non- invasive screening of early tumor-associated perturbations in cellular metabolism. METHODS: Urine samples from patients with esophageal carcinoma (n = 44), Barrett's esophagus (n = 31), and healthy controls (n = 75) were examined using (1)H-NMR spectroscopy. Targeted profiling of spectra using Chenomx software permitted quantification of 66 distinct metabolites. Unsupervised (principal component analysis) and supervised (orthogonal partial least-squares discriminant analysis OPLS-DA) multivariate pattern recognition techniques were applied to discriminate between samples using SIMCA-P(+) software. Model specificity was also confirmed through comparison with a pancreatic cancer cohort (n = 32). RESULTS: Clear distinctions between esophageal cancer, Barrett's esophagus and healthy controls were noted when OPLS-DA was applied. Model validity was confirmed using two established methods of internal validation, cross-validation and response permutation. Sensitivity and specificity of the multivariate OPLS-DA models were summarized using a receiver operating characteristic curve analysis and revealed excellent predictive power (area under the curve = 0.9810 and 0.9627 for esophageal cancer and Barrett's esophagus, respectively). The metabolite expression profiles of esophageal cancer and pancreatic cancer were also clearly distinguishable with an area under the receiver operating characteristics curve (AUROC) = 0.8954. CONCLUSIONS: Urinary metabolomics identified discrete metabolic signatures that clearly distinguished both Barrett's esophagus and esophageal cancer from controls. The metabolite expression profile of esophageal cancer was also discrete from its precursor lesion, Barrett's esophagus. The cancer-specific nature of this profile was confirmed through comparison with pancreatic cancer. These preliminary results suggest that urinary metabolomics may have a future potential role in non-invasive screening in these conditions.

Metabolomics and surgical oncology: Potential role for small molecule biomarkers.

Metabolomics, the newest of the "omics" sciences, has brought much excitement to the field of oncology as a potential new translational tool capable of bringing the molecular world of cancer care to the bedside. While still early in its development, metabolomics could alter the scope and role of surgery in the multidisciplinary treatment of cancer. This review examines potential roles of metabolomics in areas of early cancer detection, personalized therapeutics and tumorigenesis.

Trypanosome trans-sialidase mediates neuroprotection against oxidative stress, serum/glucose deprivation, and hypoxia-induced neurite retraction in Trk-expressing PC12 cells.

Trypanosome trans-sialidase (TS) is a sialic acid-transferring enzyme and a novel ligand of tyrosine kinase (TrkA) receptors but not of neurotrophin receptor p75NTR. Here, we show that TS targets TrkB receptors on TrkB-expressing pheochromocytoma PC12 cells and colocalizes with TrkB receptor internalization and phosphorylation (pTrkB). Wild-type TS but not the catalytically inactive mutant TSDeltaAsp98-Glu induces pTrkB and mediates cell survival responses against death caused by oxidative stress in TrkA- and TrkB-expressing cells like those seen with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). These same effects are not observed in Trk deficient PC12(nnr5) cells, but are re-established in PC12(nnr5) cells stably transfected with TrkA or TrkB, are partially blocked by inhibitors of tyrosine kinase (K-252a), mitogen-activated protein/mitogen-activated kinase (PD98059) and completely blocked by LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K). Both TrkA- and TrkB-expressing cells pretreated with TS or their natural ligands are protected against cell death caused by serum/glucose deprivation or from hypoxia-induced neurite retraction. The cell survival effects of NGF and BDNF against oxidative stress are significantly inhibited by the neuraminidase inhibitor, Tamiflu. Together, these observations suggest that trypanosome TS mimics neurotrophic factors in cell survival responses against oxidative stress, hypoxia-induced neurite retraction and serum/glucose deprivation.