Tissue Metablomics by High-Resolution 1H NMR Spectroscopy: Discovery of Colon Cancer-Specific Metabolomic Biomarkers.
Michael H Roehrl, Sidney S Wang, Julia Y Wang. Boston Medical Center, MA; Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Background: Colorectal cancer remains among the top causes of cancer mortality. Metabolomics, the comprehensive global characterization of small molecules involved in cellular biochemical transformations, is a powerful epigenetic approach to understanding the functional pathobiology of cancer and its underlying metabolic aberrations. High-resolution liquid proton (1H) nuclear magnetic resonance (NMR) spectroscopy is a sophisticated biophysical technique that allows a global, sensitive, and non-destructive interrogation of metabolomes extracted from human tissues.
Design: 40 paired samples of fresh cancerous and adjacent normal colonic tissues were chemically extracted by a methanol-chloroform-water mixture. Tissue metablomes were partitioned into aqueous and organic phases and subsequently examined by high-resolution 1H NMR. Fourier-transformed spectra were binned, normalized, and analyzed for statistically significant differences between normal and cancer groups. Principal component analysis (PCA) and partial least squares (PLS) discriminant analysis were used to distinguish normal spectra from cancer and to develop cancer biomarker models.
Results: PCA and PLS discriminant analysis highly successfully distinguished normal spectra from cancer. Studies of organic spectra indicated that cholesterol, cholesterol esters, and phospholipids were elevated in cancer samples, while triacylglycerol levels were depressed. Poly-unsaturated lipids also appeared predominantly in tumor biopsies, whereas mono-unsaturated lipids were more common in normal colon tissue. Analysis of aqueous samples showed increased quantities of uridine diphosphate N-acetyl-D-glucosamine, uracil, proline, lactate, O-phosphoethanolamine, glutamate, aspartate, oxidized glutathione, inosine monophosphate, and taurine in cancer spectra. In contrast, the metabolites glucose, myo-inositol, creatine, and scyllo-inositol were more prominent in normal spectra.
Conclusions: We discovered quantiative and qualitative metabolite biomarkers of human colorectal cancer. Using bioinformatics to map metabolomic differences onto network models of cellular metabolism, intriguing connections were discovered that hint at concerted large-scale metabolic readjustments in tumors and that provide exciting new directions for diagnostic test and drug target development. We show that metabolomics is a powerful and promising novel experimental approach and adds to the the toolbox of systems pathology of disease.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Monday, February 28, 2011 1:00 PM
Poster Session II # 250, Monday Afternoon