Metabolic profiling of Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) tissue by 1H-NMR analysis:: Evidence for unusual phospholipid metabolism
Metabolic profiling of Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) tissue by 1H-NMR analysis:: Evidence for unusual phospholipid metabolism
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DOI：
10.1002/pros.20761
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发表时间：
2008-07-01
期刊：
影响因子：
2.8
通讯作者：
Keun, Hector C.
中科院分区：
文献类型：
--
作者：
Teichert, Friederike;Verschoyle, Richard D.;Keun, Hector C.
背景。转基因小鼠前列腺腺癌（TRAMP）小鼠模型经常用于具有化疗/化学预防原理的临床前研究。本研究使用基于h -1核磁共振的代谢谱对该假设进行了验证，发现TRAMP肿瘤代谢表型与报道的人类前列腺癌相似。采用H-1-NMR对8周（“年轻”）或28周（“年老”）C57BL/6J野生型小鼠正常前列腺的水提取物或完整组织或年龄匹配的TRAMP小鼠前列腺肿瘤进行分析。结果与免疫组化结果比较。在蛋白和mRNA水平上研究了胆碱激酶的表达。表现为带状增生的年轻TRAMP小鼠，甘油磷胆碱（GPC）与磷脂胆碱（PC）的比值比野生型小鼠低22% （P < 0.05）。在恶性肿瘤明确的老年TRAMP小鼠中，与正常前列腺相比，肿瘤中柠檬酸盐（49%）、胆碱（33%）、PC（57%）、GPC（66%）和甘油磷酸肌醇（61%）的水平降低（P < 0.05）。分层聚类分析的代谢物水平区分正常和恶性组织在老年小鼠，而不是年轻小鼠。虽然组织柠檬酸盐的减少与人类前列腺癌相似，但与人类前列腺癌相比，TRAMP肿瘤中胆碱种类的低水平表明磷脂代谢不典型。前列腺癌中过度表达的胆碱激酶的表达与正常前列腺组织无明显差异。尽管TRAMP小鼠的前列腺癌与人类有一些共同的代谢特征，但在胆碱磷脂代谢方面有所不同，这可能会影响生物标志物或化疗/化学预防研究结果的解释。
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 H-1-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 H-1-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.CONCLUSION. 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.