Biomarkers of coordinate metabolic reprogramming in colorectal tumors in mice and humans.
OBJECTIVE
There are no robust noninvasive methods for colorectal cancer screening and diagnosis. Metabolomic and gene expression analyses of urine and tissue samples from mice and humans were used to identify markers of colorectal carcinogenesis.


METHODS
Mass spectrometry-based metabolomic analysis of urine and tissues from wild-type C57BL/6J and Apc(Min/+) mice, as well as from mice with azoxymethane-induced tumors, was employed in tandem with gene expression analysis. Metabolic profiling was also performed on colon tumor and adjacent nontumor tissues from 39 patients. The effects of β-catenin activity on metabolic profiles were assessed in mice with colon-specific disruption of Apc.


RESULTS
Thirteen markers were found in urine associated with development of colorectal tumors in Apc(Min/+) mice. Metabolites related to polyamine metabolism, nucleic acid metabolism, and methylation, identified tumor-bearing mice with 100% accuracy, and also accurately identified mice with polyps. Changes in gene expression in tumor samples from mice revealed that derangement of metabolites were a reflection of coordinate metabolic reprogramming in tumor tissue. Similar changes in urinary metabolites were observed in mice with azoxymethane-induced tumors and in mice with colon-specific activation of β-catenin. The metabolic alterations indicated by markers in urine, therefore, appear to occur during early stages of tumorigenesis, when cancer cells are proliferating. In tissues from patients, tumors had stage-dependent increases in 17 metabolites associated with the same metabolic pathways identified in mice. Ten metabolites that were increased in tumor tissues, compared with nontumor tissues (proline, threonine, glutamic acid, arginine, N1-acetylspermidine, xanthine, uracil, betaine, symmetric dimethylarginine, and asymmetric-dimethylarginine), were also increased in urine from tumor-bearing mice.


CONCLUSIONS
Gene expression and metabolomic profiles of urine and tissue samples from mice with colorectal tumors and of colorectal tumor samples from patients revealed pathways associated with derangement of specific metabolic pathways that are indicative of early-stage tumor development. These urine and tissue markers might be used in early detection of colorectal cancer.
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Soumen K
SK
Manna
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Naoki
N
Tanaka
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Kristopher W
KW
Krausz
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Majda
M
Haznadar
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Xiang
X
Xue
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Tsutomu
T
Matsubara
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Elise D
ED
Bowman
Departments of Internal Medicine, Pathology and Human Genetics, University of Michigan, Ann Arbor, Michigan.
Eric R
ER
Fearon
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Curtis C
CC
Harris
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
Yatrik M
YM
Shah
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Electronic address: gonzalef@mail.nih.gov.
Frank J
FJ
Gonzalez
D000818:Animals; D001397:Azoxymethane; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D049109:Cell Proliferation; D056148:Chromatography, Reverse-Phase; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000652:urine; D004195:Disease Models, Animal; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D057166:High-Throughput Screening Assays; D006801:Humans; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization
D014408:Biomarkers, Tumor; D001397:Azoxymethane
Apc(Min/+); Azoxymethane; Cancer Biomarker; Colorectal Cancer; Metabolic Reprogramming; Metabolomics