Metabolomic Changes Accompanying Transformation and Acquisition of Metastatic Potential in a Syngeneic Mouse Mammary Tumor Model

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Feb 9

PMID 20139083

Citations 58

Authors

Xin Lu

Bryson Bennet

Euphemia Mu

Joshua Rabinowitz

Yibin Kang

Affiliations

Soon will be listed here.

Abstract

Breast cancer is the most common cancer type for women in the western world. Despite decades of research, the molecular processes associated with breast cancer progression are still inadequately defined. Here, we focus on the systematic alteration of metabolism by using the state of the art metabolomic profiling techniques to investigate the changes of 157 metabolites during the progression of normal mouse mammary epithelial cells to an isogenic series of mammary tumor cell lines with increasing metastatic potentials. Our results suggest a two-step metabolic progression hypothesis during the acquisition of tumorigenic and metastatic abilities. Metabolite changes accompanying tumor progression are identified in the intracellular and secreted forms in several pathways, including glycolysis, the tricarboxylic acid cycle, the pentose phosphate pathway, fatty acid and nucleotide biosynthesis, and the GSH-dependent antioxidative pathway. These results suggest possible biomarkers of breast cancer progression as well as opportunities of interrupting tumor progression through the targeting of metabolic pathways.

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References

Warburg O, Wind F, Negelein E . THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol. 2009; 8(6):519-30. PMC: 2140820. DOI: 10.1085/jgp.8.6.519. View

Filomeni G, Rotilio G, Ciriolo M . Cell signalling and the glutathione redox system. Biochem Pharmacol. 2002; 64(5-6):1057-64. DOI: 10.1016/s0006-2952(02)01176-0. View

Minn A, Gupta G, Siegel P, Bos P, Shu W, Giri D . Genes that mediate breast cancer metastasis to lung. Nature. 2005; 436(7050):518-24. PMC: 1283098. DOI: 10.1038/nature03799. View

Hahn W, Weinberg R . Modelling the molecular circuitry of cancer. Nat Rev Cancer. 2002; 2(5):331-41. DOI: 10.1038/nrc795. View

Sonveaux P, Vegran F, Schroeder T, Wergin M, Verrax J, Rabbani Z . Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008; 118(12):3930-42. PMC: 2582933. DOI: 10.1172/JCI36843. View

Luo B, Groenke K, Takors R, Wandrey C, Oldiges M . Simultaneous determination of multiple intracellular metabolites in glycolysis, pentose phosphate pathway and tricarboxylic acid cycle by liquid chromatography-mass spectrometry. J Chromatogr A. 2007; 1147(2):153-64. DOI: 10.1016/j.chroma.2007.02.034. View

Griffin J, Shockcor J . Metabolic profiles of cancer cells. Nat Rev Cancer. 2004; 4(7):551-61. DOI: 10.1038/nrc1390. View

Lu X, Kang Y . Organotropism of breast cancer metastasis. J Mammary Gland Biol Neoplasia. 2007; 12(2-3):153-62. DOI: 10.1007/s10911-007-9047-3. View

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T . Cancer statistics, 2008. CA Cancer J Clin. 2008; 58(2):71-96. DOI: 10.3322/CA.2007.0010. View

10.

Kang Y . New tricks against an old foe: molecular dissection of metastasis tissue tropism in breast cancer. Breast Dis. 2007; 26:129-38. DOI: 10.3233/bd-2007-26111. View

11.

Richardson A, Yang C, Osterman A, Smith J . Central carbon metabolism in the progression of mammary carcinoma. Breast Cancer Res Treat. 2007; 110(2):297-307. PMC: 2440942. DOI: 10.1007/s10549-007-9732-3. View

12.

Griffith O, Meister A . Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine). J Biol Chem. 1979; 254(16):7558-60. View

13.

Aslakson C, Miller F . Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 1992; 52(6):1399-405. View

14.

Gupta G, Massague J . Cancer metastasis: building a framework. Cell. 2006; 127(4):679-95. DOI: 10.1016/j.cell.2006.11.001. View

15.

Zu X, Guppy M . Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun. 2003; 313(3):459-65. DOI: 10.1016/j.bbrc.2003.11.136. View

16.

Sreekumar A, Poisson L, Rajendiran T, Khan A, Cao Q, Yu J . Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009; 457(7231):910-4. PMC: 2724746. DOI: 10.1038/nature07762. View

17.

Kang Y . Functional genomic analysis of cancer metastasis: biologic insights and clinical implications. Expert Rev Mol Diagn. 2005; 5(3):385-95. DOI: 10.1586/14737159.5.3.385. View

18.

Bajad S, Lu W, Kimball E, Yuan J, Peterson C, Rabinowitz J . Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatography-tandem mass spectrometry. J Chromatogr A. 2006; 1125(1):76-88. DOI: 10.1016/j.chroma.2006.05.019. View

19.

Christofk H, Vander Heiden M, Wu N, Asara J, Cantley L . Pyruvate kinase M2 is a phosphotyrosine-binding protein. Nature. 2008; 452(7184):181-6. DOI: 10.1038/nature06667. View

20.

Filomeni G, Rotilio G, Ciriolo M . Glutathione disulfide induces apoptosis in U937 cells by a redox-mediated p38 MAP kinase pathway. FASEB J. 2002; 17(1):64-6. DOI: 10.1096/fj.02-0105fje. View