Skip to main content
Article thumbnail
Location of Repository

Approaches to the discovery of biomarkers of prostate carcinogenesis in TRAMP mice and of chemopreventive efficacy of tea polyphenols

By Friederike Teichert


To improve prostate cancer management in humans who have, or are at risk of\ud developing, the disease, biomarkers are required to aid early diagnosis and\ud monitoring of response to chemotherapeutic or chemopreventive intervention.\ud In this project metabonomic and peptidomic approaches were used to study\ud biological changes associated with prostate carcinogenesis in a transgenic mouse\ud model (TRAMP, TRansgenic Adenocarcinoma of the Mouse Prostate). Observed\ud changes were compared with pathological alterations. Metabolome and peptidome\ud analyses were conducted in TRAMP mice exposed to chemopreventive intervention\ud with green tea polyphenols (GTP). Effects of consumption of GTP or black tea\ud theaflavins on the plasma and urine metabonome/peptidome in patients with benign\ud prostatic hyperplasia (BPH) were also investigated. Oxidative stress status reflected\ud by urinary 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) was assessed in mice\ud and humans on tea polyphenols.\ud Metabonomic profiling revealed that at early stages of carcinogenesis in mice,\ud alterations of tumour levels of choline metabolites resembled the human disease. In\ud contrast, in advanced stages of TRAMP prostate carcinogenesis, phospholipid\ud metabolism is affected differently by malignancy than in its human counterpart.\ud Disturbed prostate-specific citrate metabolism seems common to both human and\ud TRAMP prostate tumours when compared to normal tissue. These results suggest\ud that the TRAMP mouse may be a better model with respect to humans of early stage\ud carcinogenesis with minor proliferative lesions than of more advanced stages of\ud malignancy.\ud Urinary 8-oxodG levels were not affected by presence of prostate cancer or\ud intervention with tea. Metabolic profiling gave evidence for an effect of GTP on\ud energy metabolism in both mice and humans. Although TRAMP and GTP-groupspecific\ud metabonomic and peptidomic changes were found in plasma and urine, none\ud of these metabolites or peptides could be unambiguously identified as biomarkers of\ud carcinogenesis or GTP exposure. Among possible confounding factors which should\ud be taken into consideration in future metabonomic/peptidomic studies is the host’s\ud gut microflora

Publisher: University of Leicester
Year: 2008
OAI identifier:

Suggested articles


  1. (2004). A 1H NMRbased metabonomic study of urine and plasma samples obtained from healthy human subjects.
  2. (1998). A comprehensive urinary metabolomic approach for identifying kidney cancer. Analytical Biochemistry 363, 185-Klaunig,
  3. (2005). a p53-inducible regulator of glycolysis and apoptosis.
  4. (2007). A probasin-large T antigen transgenic mouse line develops prostate adenocarcinoma and neuroendocrine carcinoma with metastatic potential.
  5. (2005). A prospective clinical trial of green tea for hormone refractory prostate cancer: An evaluation of the complementary/alternative therapy approach.
  6. A relational database for sequence-specificproteinNMRdata.
  7. A statistical framework for the design of microarray experiments and effective detection of differential gene expression.
  8. Albanese C. In vivo magnetic resonance volumetric and spectroscopic analysis ofmouseprostate cancermodels.
  9. (2005). An improved liquid chromatography/tandem mass spectrometry method for the determination of 8-oxo-7,8-dihydro-2 '-deoxyguanosine in DNA samples using immunoaffinity column purification.
  10. (2006). an oxidized purine nucleoside triphosphatase, prevents the cytotoxicity and neurotoxicity of oxidized purine nucleotides.
  11. (1979). Analysis of a form of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, as a marker of cellular oxidative stress during carcinogenesis.
  12. (2006). Application in 1H NMR metabonomics.
  13. (2006). Assessment of analytical reproducibility of 1H NMR spectroscopy based metabonomics for large-scale epidemiological research: The INTERMAP study.
  14. Bhujwalla ZM.Molecular causes of the aberrant choline phospholipid metabolism in breast cancer.
  15. (2004). Bioavailability of soybean isoflavones depends upon gut microflora in women.
  16. (1994). Bioenergetic theory of prostate malignancy.
  17. (1994). Biofluid 1H NMR-based metabonomic techniques in nutrition research metabolic effects of dietary isoflavones in humans.
  18. (2002). Boosted decision tree analysis of surface-enhanced laser desorption/ionization mass spectral serum profiles discriminates prostate cancer from noncancer patients.
  19. (2006). Cancer progression in the transgenic adenocarcinoma of mouse prostate mouse is related to energy balance, body mass, and body composition, but not food intake.
  20. (2006). Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: A preliminary report from a one-year proof-of-principle study.
  21. (2004). Choline kinase activation is a critical requirement for the proliferation of primary human mammary epithelial cells and breast tumor progression. Cancer Res
  22. Citrate alterations in primary andmetastatic human prostatic adenocarcinomas: 1H magnetic resonance spectroscopy and biochemical study.
  23. (1993). Combined magnetic resonance imaging and spectroscopic imaging approach to molecular imaging of prostate cancer.
  24. (2005). Comparative metabonomics of differential hydrazine toxicity in the rat and mouse. Toxicology and Applied Pharmacology 204,
  25. (2007). Detection of pre-neoplastic and neoplastic prostate disease by MADI profiling of urine.
  26. (2007). Determination of creatinine in urine by tandem mass spectrometry. Clinica Chimica Acta 350,
  27. (1992). Deviant energetic metabolism of glycolytic cancer cells.
  28. (2003). Diagnostic potential of serum proteomic patterns in prostate cancer.
  29. (2002). Differential expression of cholinephosphotransferase in normal and cancerous human mammary epithelial cells. Biochem Biophys Res Commun
  30. (2005). DNA repair is responsible for the presence of oxidatively damaged DNA lesions in urine.
  31. (2001). Does oxidative damage to DNA increase with age?
  32. (2007). E-mail: Copyright #
  33. (2003). Effect of increased tea consumption on oxidative DNA damage among smokers: A randomized controlled study.
  34. (2007). Epigallocatechin-3-gallate suppresses early stage, but not late stage prostate cancer in TRAMP mice: Mechanisms of action.
  35. Evaluation of the cancer chemopreventive efficacy of rice bran in genetic mouse models of breast, prostate and intestinal carcinogenesis.
  36. (1989). Exercise and green tea extract stimulate fat oxidation and prevent obesity in mice.
  37. Expression and characterization of the active molecular forms of choline/ethanolamine kinase-alpha and -beta in mouse tissues, including carbon tetrachloride-induced liver.
  38. (2005). extract improves endurance capacity and increases muscle lipid oxidation in mice.
  39. Fast receptor-induced formation of glycerophosphoinositol-4-phosphate, a putative novel intracellular messenger in the Ras pathway.
  40. (1995). Generation and elimination of 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate, a mutagenic substrate for DNA-synthesis, in human cells.
  41. (2004). Genetically defined mouse models that mimic natural aspects of human prostate cancer development.
  42. (2002). Glycerophosphocholine metabolism in higher plant cells. Evidence of a new glycerylphosphodiester phosphodiesterase.
  43. Glycerophosphoinositols inhibit the ability of tumour cells to invade the extracellular matrix.
  44. HeWL,Halpern EF,McDougal WS, Wu CL. Metabolic characterization of human prostate cancerwith tissuemagnetic resonance spectroscopy.
  45. (1998). High resolution magic angle spinning 1H nuclear magnetic resonance analysis of intact prostatic hyperplastic and tumour tissues.
  46. (2005). HPLC-MS-based methods for the study of metabonomics.
  47. (2007). Huntingdon Life Science, East Millstone,
  48. (2006). Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.
  49. (2006). In vivo magnetic resonance volumetric and spectroscopic analysis of mouse prostate cancer models.
  50. (2006). Inhibition of DNA methyltransferase activity prevents tumorigenesis in a mouse model of prostate cancer.
  51. Inhibitionof prostate carcinogenesis in TRAMPmice by oral infusion of green tea polyphenols.
  52. (2007). Investigation of analytical variation in metabonomic analysis using liquid chromatography/mass spectrometry.
  53. (2005). lifestyle and risk of prostate cancer.
  54. (1993). Localized proton MR spectroscopy of citrate in vitro and of the human prostate in vivo at 1.5 T. Magn Reson Med
  55. (2004). Malabsorption syndrome with and without small intestinal bacterial overgrowth: A study on upper-gut aspirate using 1H NMR spectroscopy.
  56. Malignant transformation by ras and other oncogenes produces common alterations in inositol phospholipid signaling pathways.
  57. (1989). mammalian metabolism and personalized health care.
  58. (2005). Metabolic characterization of human prostate cancer with tissue magnetic resonance spectroscopy.
  59. (1996). Metabolite profiling by one- and two-dimensional NMR analysis of complex mixtures.
  60. (2003). Metabonomic analysis of mouse urine by liquid-chromatography- time of flight mass spectrometry (LC-TOFMS): Detection of strain, diurnal and gender differences.
  61. (2006). Metabonomics approach to determine metabolic differences between green tea and black tea consumption.
  62. (2005). Metabonomics in Toxicity Assessment.
  63. (1996). Metastatic prostate cancer in a transgenic mouse.
  64. Mitochondrial dysfunction in cancer.
  65. Modulation of cholinephosphotransferase activity inbreast cancer cell linesbyRo5-4864, aperipheral benzodiazepine receptor agonist.
  66. (2003). NMR-based metabonomic studies on the biochemical effects of epicatechin in the rat.
  67. (2002). noninvasive diagnosis of the presence and severity of coronary heart disease using 1H NMR-based metabonomics.
  68. (2005). Noninvasive magnetic resonance spectroscopic pharmacodynamic markers of the choline kinase inhibitor MN58b in human carcinoma models.
  69. Nuclear medicine studies of the prostate, testes, and bladder.
  70. Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers.
  71. (1889). Oxidative damage to DNA during aging - 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine.
  72. (2004). Oxidative DNA damage and disease: induction, repair and significance.
  73. p53 regulates mitochondrial respiration.
  74. (2003). Pathological and molecular aspects of prostate cancer.
  75. (2006). Phospholipid capture combined with non-linear chromatographic correction for improved serum metabolite profiling.
  76. (2002). Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging.
  77. (2006). Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics. Anal Chem
  78. (1998). progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: A model for prostate cancer.
  79. Promoter deletion and loss of retinoblastoma gene expression in human prostate carcinoma.
  80. (1993). Prostate cancer epidemiology.
  81. Prostate cancer in a transgenic mouse.
  82. (2003). ProtonHR-MAS spectroscopy and quantitative pathologic analysis of MRI/3DMRSI-targeted postsurgical prostate tissues. Magn Reson Med
  83. (2003). Purification of peptides from serum and cell lysates for mass spectrometry. Millipore -Technical Library avilable from:,
  84. (2006). Quantitative analysis of prostate metabolites using 1H HR-MAS spectroscopy. Magnetic Resonance in
  85. (2002). Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men.
  86. (2002). Serum proteomic patterns for detection of prostate cancer.
  87. Shockcor JP.Metabolic profiles of cancer cells.NatRev Cancer 2004;4:551–561. 18. Ramı´rez de
  88. (2003). The Analyst
  89. (1982). The application of stable isotopes in biomedical research.
  90. (2006). The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: Connecting the dots. Mol Cancer
  91. (1994). The metabolism of prostate malignancy: Insight into the pathogenesis of prostate cancer and new approaches for its diagnosis and treatment.
  92. (2001). The metabolism of prostate malignancy: Insight into the pathogenesis of prostate cancer and new approaches for its diagnosis and treatment. Oncol Spectr
  93. (2005). The nucleotide pool is a significant target for oxidative stress.
  94. The Prostate Metabolic Prof|ling of TRAMPMice 1047 Investigation of analytical variation in metabonomic analysis using liquid chromatography/mass spectrometry
  95. (2006). Theaflavins inhibit prostate carcinogenesis in the TRAMP mouse model.
  96. Therapeutic targets and biomarkers identified in cancer choline phospholipid metabolism.
  97. (1996). Three-dimensional H-1 MR spectroscopic imaging of the in situ human prostate with high (0.24–0.7-cm(3)) spatial resolution. Radiology
  98. (1991). Transformation by the K-ras oncogene correlates with increases in phospholipase A2 activity, glycerophosphoinositol production and phosphoinositide synthesis in thyroid cells.
  99. Tumour metabolomics in animal models of human cancer.
  100. (1991). Two prostate carcinoma cell-lines demonstrate abnormalities in tumor suppressor genes.
  101. Ueber den Stoffwechel von Tumoren im Koerper. Klin Wochenschr 1926;5:829–832.
  102. United Kingdom Co-Ordinating Committee on Cancer Research (UKCCCR) guidelines for the welfare of animals in experimental neoplasia (second edition).
  103. (2006). Use of proteomic patterns in serum to identify ovarian cancer.
  104. (2007). versus prostate specific antigen analysis of prospective plasma samples in a nested case-control study of prostate cancer.
  105. (1990). What should a urologist know about hereditary predisposition to prostate cancer?
  106. (2008). whole plant extract on piglet intestinal ecosystem.
  107. (2005). Why do tumour cells glycolyse?’: Fromglycolysis through citrate to lipogenesis.MolCell Biochem

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.