Approaches to the discovery of biomarkers of prostate carcinogenesis in TRAMP mice and of chemopreventive efficacy of tea polyphenols
thesisposted on 25.11.2011, 11:15 by Friederike Teichert
To improve prostate cancer management in humans who have, or are at risk of developing, the disease, biomarkers are required to aid early diagnosis and monitoring of response to chemotherapeutic or chemopreventive intervention. In this project metabonomic and peptidomic approaches were used to study biological changes associated with prostate carcinogenesis in a transgenic mouse model (TRAMP, TRansgenic Adenocarcinoma of the Mouse Prostate). Observed changes were compared with pathological alterations. Metabolome and peptidome analyses were conducted in TRAMP mice exposed to chemopreventive intervention with green tea polyphenols (GTP). Effects of consumption of GTP or black tea theaflavins on the plasma and urine metabonome/peptidome in patients with benign prostatic hyperplasia (BPH) were also investigated. Oxidative stress status reflected by urinary 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG) was assessed in mice and humans on tea polyphenols. Metabonomic profiling revealed that at early stages of carcinogenesis in mice, alterations of tumour levels of choline metabolites resembled the human disease. In contrast, in advanced stages of TRAMP prostate carcinogenesis, phospholipid metabolism is affected differently by malignancy than in its human counterpart. Disturbed prostate-specific citrate metabolism seems common to both human and TRAMP prostate tumours when compared to normal tissue. These results suggest that the TRAMP mouse may be a better model with respect to humans of early stage carcinogenesis with minor proliferative lesions than of more advanced stages of malignancy. Urinary 8-oxodG levels were not affected by presence of prostate cancer or intervention with tea. Metabolic profiling gave evidence for an effect of GTP on energy metabolism in both mice and humans. Although TRAMP and GTP-groupspecific metabonomic and peptidomic changes were found in plasma and urine, none of these metabolites or peptides could be unambiguously identified as biomarkers of carcinogenesis or GTP exposure. Among possible confounding factors which should be taken into consideration in future metabonomic/peptidomic studies is the host’s gut microflora.