Metabolic profiling of transgenic adenocarcinoma of mouse prostate (TRAMP) tissue by 1H-NMR analysis: evidence for unusual phospholipid metabolism.
BACKGROUND
The TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse model has frequently been used in preclinical studies with chemotherapeutic/chemopreventive rationales. Here the hypothesis was tested using (1)H-NMR-based metabolic profiling that the TRAMP tumor metabolic phenotype resembles that reported for human prostate cancer.


METHODS
Aqueous extracts or intact tissues of normal prostate from 8- ("young") or 28-("old") week-old C57BL/6J wild-type mice or of prostate tumor from age-matched TRAMP mice were analyzed by (1)H-NMR. Results were compared with immunohistochemical findings. Expression of choline kinase was studied at the protein and mRNA levels.


RESULTS
In young TRAMP mice presenting with zonal hyperplasia, the ratio of glycerophosphocholine (GPC) to phosphocholine (PC) was 22% below that in wild-type mice (P < 0.05). In old TRAMP mice with well-defined malignancy, reduced tumor levels of citrate (49%), choline (33%), PC (57%), GPC (66%), and glycerophosphoinositol (61%) were observed relative to normal prostate (P < 0.05). Hierarchical cluster analysis of metabolite levels distinguished between normal and malignant tissue in old but not young mice. While the reduction in tissue citrate resembles human prostate cancer, low levels of choline species in TRAMP tumors suggest atypical phospholipid metabolism as compared to human prostate cancer. TRAMP tumor and normal prostate tissues did not differ in expression of choline kinase, which is overexpressed in human prostate cancer.


CONCLUSIONS
Although prostate cancer in TRAMP mice shares some metabolic features with that in humans, it differs with respect to choline phospholipid metabolism, which could impact upon the interpretation of results from biomarker or chemotherapy/chemoprevention studies.
Teichert
Friederike
F
Cancer Biomarkers and Prevention Group, University of Leicester, Leicester, UK.
Verschoyle
Richard D
RD
Greaves
Peter
P
Edwards
Richard E
RE
Teahan
Orla
O
Jones
Donald J L
DJ
Wilson
Ian D
ID
Farmer
Peter B
PB
Steward
William P
WP
Gant
Timothy W
TW
Gescher
Andreas J
AJ
Keun
Hector C
HC
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D014408:Biomarkers, Tumor; D002794:Choline / Q000378:metabolism; D002797:Choline Kinase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005997:Glycerylphosphorylcholine / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods*; D020411:Oligonucleotide Array Sequence Analysis; D010713:Phosphatidylcholines / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D010767:Phosphorylcholine / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011522:Protons
D014408:Biomarkers, Tumor; D010713:Phosphatidylcholines; D010743:Phospholipids; D011522:Protons; D010767:Phosphorylcholine; D005997:Glycerylphosphorylcholine; D002797:Choline Kinase; D002794:Choline