1H NMR metabolomics identification of markers of hypoxia-induced metabolic shifts in a breast cancer model system
- 1k Downloads
Hypoxia can promote invasive behavior in cancer cells and alters the response to therapeutic intervention as a result of changes in the expression many genes, including genes involved in intermediary metabolism. Although metabolomics technologies are capable of simultaneously measuring a wide range of metabolites in an untargeted manner, these methods have been relatively under utilized in the study of cancer cell responses to hypoxia. Thus, 1H NMR metabolomics was used to examine the effects of hypoxia in the MDA-MB-231 human breast cancer cell line, both in vitro and in vivo. Cell cultures were compared with respect to their metabolic responses during growth under either hypoxic (1% O2) or normoxic conditions. Orthogonal partial least squares discriminant analysis (OPLS-DA) was used to identify a set of metabolites that were responsive to hypoxia. Via intracardiac administration, MDA-MB-231 cells were also used to generate widespread metastatic disease in immuno-compromised mice. Serum metabolite analysis was conducted to compare animals with and without a large tumor burden. Intriguingly, using a cross-plot of the OPLS loadings, both the in vitro and in vivo samples yielded a subset of metabolites that were significantly altered by hypoxia. These included primarily energy metabolites and amino acids, indicative of known alterations in energy metabolism, and possibly protein synthesis or catabolism. The results suggest that the metabolite pattern identified might prove useful as a marker for intra-tumoral hypoxia.
KeywordsMetabolomics 1H NMR spectroscopy Hypoxia Glycolysis Breast cancer Chemometrics OPLS-DA Tumor xenograft
Hypoxia inducible factor
Orthogonal partial least squares discriminant analysis
Principal component analysis
Variable influence on projection
The Metabolomics Research Centre at the University of Calgary is supported by funding from Alberta Health Services (AHS)/The Alberta Cancer Foundation (ACF). The studies were also supported in part by a translational grant from the AHS/ACF (to F.R.J.); F.R.J was the recipient of a Canada Research Chairs award.
- Eisner R, Stretch C, Eastman T, Xia J, Hau D (2010) Learning to predict cancer-associated skeletal muscle wasting from 1H-NMR profiles of urinary metabolites. Metabolomics (in press)Google Scholar
- Griffiths JR, McSheehy PM, Robinson SP, Troy H, Chung YL, Leek RD, Williams KJ, Stratford IJ, Harris AL, Stubbs M (2002) Metabolic changes detected by in vivo magnetic resonance studies of HEPA-1 wild-type tumors and tumors deficient in hypoxia-inducible factor-1beta (HIF-1beta): evidence of an anabolic role for the HIF-1 pathway. Cancer Res 62:688–695Google Scholar
- Sonveaux P, Végran F, Schroeder T, Wergin MC et al (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942Google Scholar
- Weljie AM, Jirik FR (2010) Hypoxia-induced metabolic shifts in cancer cells: moving beyond the Warburg effect. Int J Biochem cell biolGoogle Scholar