Global metabolomics analysis has the potential to uncover novel metabolic pathways that are differentially regulated during carcinogenesis, aiding in biomarker discovery for early diagnosis and remission monitoring. Metabolomics studies with human samples can be problematic due to high inter-individual variation; however xenografts of human cancers in mice offer a well-controlled model system. Urine was collected from a xenograft mouse model of MCF-7 breast cancer and analyzed by mass spectrometry-based metabolomics to identify metabolites associated with cancer progression. Over 10 weeks, 24 h urine was collected weekly from control mice, mice dosed with estradiol cypionate (1 mg/mL), mice inoculated with MCF-7 cells (1 × 10 7) and estradiol cypionate (1 mg/mL), and mice dosed with MCF-7 cells (1 × 10 7) only (n = 10/group). Mice that received both estradiol cypionate and MCF-7 cells developed tumors from four weeks after inoculation. Five urinary metabolites were identified that were associated with breast cancer; enterolactone glucuronide, coumaric acid sulfate, capric acid glucuronide, an unknown metabolite, and a novel mammalian metabolite, “taurosebacic acid”. These metabolites revealed a correlation between tumor growth, fatty acid synthesis, and potential anti-proliferative effects of gut microbiota-metabolized food derivatives. These biomarkers may be of value for early diagnosis of cancer, monitoring of cancer therapeutics, and may also lead to future mechanistic studies.
References
[1]
American Cancer Society: Cancer Facts and Figures 2013. Available online: http://www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2013/index/ (accessed on 21 June 2013).
[2]
IARC. World Cancer Report 2009; International Agency for Research on Cancer: Lyon, France, 2008.
[3]
Denkert, C.; Bucher, E.; Hilvo, M.; Salek, R.; Oresc, M.; Griffin, J.; Brockmoller, S.; Klauschen, F.; Loibl, S.; Barupal, D.K.; et al. Metabolomics of human breast cancer: New approaches for tumor typing and biomarker discovery. Genome Med. 2012, 4, 37.
[4]
Slupsky, C.M.; Steed, H.; Wells, T.H.; Dabbs, K.; Schepansky, A.; Capstick, V.; Faught, W.; Sawyer, M.B. Urine metabolite analysis offers potential early diagnosis of ovarian and breast cancers. Clin. Cancer Res. 2010, 16, 5835–5841, doi:10.1158/1078-0432.CCR-10-1434.
[5]
Woo, H.M.; Kim, K.M.; Choi, M.H.; Jung, B.H.; Lee, J.; Kong, G.; Nam, S.J.; Kim, S.; Bai, S.W.; Chung, B.C. Mass spectrometry based metabolomic approaches in urinary biomarker study of women's cancers. Clin. Chim. Acta. 2009, 400, 63–69, doi:10.1016/j.cca.2008.10.014.
[6]
Johnson, C.H.; Patterson, A.D.; Idle, J.R.; Gonzalez, F.J. Xenobiotic metabolomics: Major impact on the metabolome. Annu. Rev. Pharmacol. Toxicol. 2012, 52, 37–56, doi:10.1146/annurev-pharmtox-010611-134748.
[7]
Moroz, J.; Turner, J.; Slupsky, C.; Fallone, G.; Syme, A. Tumour xenograft detection through quantitative analysis of the metabolic profile of urine in mice. Phys. Med. Biol. 2011, 56, 535–556, doi:10.1088/0031-9155/56/3/002.
[8]
Kim, K.B.; Yang, J.Y.; Kwack, S.J.; Park, K.L.; Kim, H.S.; Ryu do, H.; Kim, Y.J.; Hwang, G.S.; Lee, B.M. Toxicometabolomics of urinary biomarkers for human gastric cancer in a mouse model. J. Toxicol. Env. Heal. A 2010, 73, 1420–1430, doi:10.1080/15287394.2010.511545.
[9]
Fan, T.W.; Lane, A.N.; Higashi, R.M.; Yan, J. Stable isotope resolved metabolomics of lung cancer in a SCID mouse model. Metabolomics 2011, 7, 257–269, doi:10.1007/s11306-010-0249-0.
[10]
Liu, X.P.; Suzuki, N.; Laxmi, Y.R.S.; Okamoto, Y.; Shibutani, S. Anti-breast cancer potential of daidzein in rodents. Life Sci. 2012, 91, 415–419, doi:10.1016/j.lfs.2012.08.022.
[11]
Chen, X.S.; Meng, Q.W.; Zhao, Y.B.; Liu, M.Y.; Li, D.D.; Yang, Y.M.; Sun, L.C.; Sui, G.J.; Cai, L.; Dong, X.Q. Angiotensin II type 1 receptor antagonists inhibit cell proliferation and angiogenesis in breast cancer. Cancer Lett. 2013, 328, 318–324, doi:10.1016/j.canlet.2012.10.006.
[12]
Chen, J.M.; Saggar, J.K.; Corey, P.; Thompson, L.U. Flaxseed cotyledon fraction reduces tumour growth and sensitises tamoxifen treatment of human breast cancer xenograft (MCF-7) in athymic mice. Brit. J. Nutr. 2011, 105, 339–347, doi:10.1017/S0007114510003557.
[13]
Plowman, J.; Dykes, D.; Hollingshead, M.; Simpson-Herren, L.; Alley, M. Human tumor xenograft models in NCI drug development. In Anticancer Drug Development Guide: Preclinical Screening, Clinical Trials, and Approval; Humana Press Inc: New York, NY, USA, 1997; pp. 101–125.
Johnson, C.H.; Patterson, A.D.; Krausz, K.W.; Kalinich, J.F.; Tyburski, J.B.; Kang, D.W.; Luecke, H.; Gonzalez, F.J.; Blakely, W.F.; Idle, J.R. Radiation metabolomics. 5. Identification of urinary biomarkers of ionizing radiation exposure in nonhuman primates by mass spectrometry-based metabolomics. Radiat. Res. 2012, 178, 328–340, doi:10.1667/RR2950.1.
[16]
Smith, C.A.; O'Maille, G.; Want, E.J.; Qin, C.; Trauger, S.A.; Brandon, T.R.; Custodio, D.E.; Abagyan, R.; Siuzdak, G. METLIN: A metabolite mass spectral database. Ther. Drug Monit. 2005, 27, 747–751, doi:10.1097/01.ftd.0000179845.53213.39.
[17]
Jakobs, C.; Sweetman, L.; Wadman, S.K.; Duran, M.; Saudubray, J.M.; Nyhan, W.L. Prenatal-diagnosis of glutaric aciduria type-II by direct chemical-analysis of dicarboxylic-acids in amniotic-fluid. Eur. J. Pediatr. 1984, 141, 153–157, doi:10.1007/BF00443213.
[18]
Gregersen, N.; Kolvraa, S.; Mortensen, P.B.; Rasmussen, K. C6-C10-dicarboxylic aciduria: Biochemical considerations in relation to diagnosis of beta-oxidation defects. Scand. J. Clin. Lab. Inv. 1982, 42, 15–27.
[19]
Sonestedt, E.; Wirfalt, E. Enterolactone and breast cancer: Methodological issues may contribute to conflicting results in observational studies. Nutr. Res. 2010, 30, 667–677, doi:10.1016/j.nutres.2010.09.010.
[20]
Penttinen, P.; Jaehrling, J.; Damdimopoulos, A.E.; Inzunza, J.; Lemmen, J.G.; van der Saag, P.; Pettersson, K.; Gauglitz, G.; Makela, S.; Pongratz, I. Diet-derived polyphenol metabolite enterolactone is a tissue-specific estrogen receptor activator. Endocrinology 2007, 148, 4875–4886, doi:10.1210/en.2007-0289.
[21]
Abarzua, S.; Serikawa, T.; Szewczyk, M.; Richter, D.U.; Piechulla, B.; Briese, V. Antiproliferative activity of lignans against the breast carcinoma cell lines MCF 7 and BT 20. Arch. Gynecol. Obstet. 2012, 285, 1145–1151, doi:10.1007/s00404-011-2120-6.
[22]
Saarinen, N.M.; Power, K.; Chen, J.; Thompson, L.U. Flaxseed attenuates the tumor growth stimulating effect of soy protein in ovariectomized athymic mice with MCF-7 human breast cancer xenografts. Int. J. Cancer 2006, 119, 925–931, doi:10.1002/ijc.21898.
[23]
Truan, J.S.; Chen, J.M.; Thompson, L.U. Comparative effects of sesame seed lignan and flaxseed lignan in reducing the growth of human breast tumors (MCF-7) at high levels of circulating estrogen in athymic mice. Nutr. Cancer 2012, 64, 65–71, doi:10.1080/01635581.2012.630165.
[24]
Truan, J.S.; Chen, J.M.; Thompson, L.U. Flaxseed oil reduces the growth of human breast tumors (MCF-7) at high levels of circulating estrogen. Mol. Nutr. Food Res. 2010, 54, 1414–1421, doi:10.1002/mnfr.200900521.
[25]
Dabrosin, C.; Chen, J.; Wang, L.; Thompson, L.U. Flaxseed inhibits metastasis and decreases extracellular vascular endothelial growth factor in human breast cancer xenografts. Cancer Lett. 2002, 185, 31–37, doi:10.1016/S0304-3835(02)00239-2.
[26]
Mabrok, H.B.; Klopfleisch, R.; Ghanem, K.Z.; Clavel, T.; Blaut, M.; Loh, G. Lignan transformation by gut bacteria lowers tumor burden in a gnotobiotic rat model of breast cancer. Carcinogenesis 2012, 33, 203–208, doi:10.1093/carcin/bgr256.
[27]
Fresco, P.; Borges, F.; Diniz, C.; Marques, M.P. New insights on the anticancer properties of dietary polyphenols. Med. Res. Rev. 2006, 26, 747–766, doi:10.1002/med.20060.
[28]
Serafim, T.L.; Carvalho, F.S.; Marques, M.P.; Calheiros, R.; Silva, T.; Garrido, J.; Milhazes, N.; Borges, F.; Roleira, F.; Silva, E.T.; et al. Lipophilic caffeic and ferulic acid derivatives presenting cytotoxicity against human breast cancer cells. Chem. Res. Toxicol. 2011, 24, 763–774, doi:10.1021/tx200126r.
[29]
Kampa, M.; Alexaki, V.I.; Notas, G.; Nifli, A.P.; Nistikaki, A.; Hatzoglou, A.; Bakogeorgou, E.; Kouimtzoglou, E.; Blekas, G.; Boskou, D.; et al. Antiproliferative and apoptotic effects of selective phenolic acids on T47D human breast cancer cells: Potential mechanisms of action. Breast Cancer Res. 2004, 6, R63–R74, doi:10.1186/bcr752.
[30]
Brozic, P.; Kocbek, P.; Sova, M.; Kristl, J.; Martens, S.; Adamski, J.; Gobec, S.; Lanisnik Rizner, T. Flavonoids and cinnamic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1. Mol. Cell. Endocrinol. 2009, 301, 229–234, doi:10.1016/j.mce.2008.09.004.
