Prostate MRI and MRS: Correlations with Gene Expression

前列腺 MRI 和 MRS：与基因表达的相关性

• 批准号: 7096391
• 负责人: SANDRA M GASTON
• 金额: $ 12.92万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096391
• 关键词: choline; clinical research; gene expression; neoplasm /cancer; prostate; prostate neoplasms

DESCRIPTION (provided by applicant): Magnetic Resonance Spectroscopy (MRS), combined with Magnetic Resonance Imaging (MRI) is a rapidly developing noninvasive technology that is under evaluation as a tool for determining prostate cancer location, stage and grade in patients with clinically organ confined disease. The metabolic changes characteristic of MRS spectra of malignant areas of the prostate gland include increased choline and decreased citrate peaks. It has been proposed that the elevated choline peak reflects tumor-associated cell membrane synthesis, with increased de novo formation of phosphatidylcholine. However, little is known about the changes in gene expression that underlie the choline spectra observed in prostate cancer. The major goal of our larger project is to identify the molecular events that correspond to MRI/MRS detectable prostate cancer. The goal of the project outlined in this proposal is to characterize the changes in gene expression that underlie the increase in MRS detectable choline in prostate cancers. In preliminary studies, we mapped the expression of choline kinase (the first and probably regulatory enzyme in the pathway for de novo synthesis of choline containing membrane lipids) in tissue-print micro-peels obtained from radical prostatectomy specimens containing Gleason grade 6,7 or 8 prostate cancer. Patterns of choline kinase expression correspond closely to that of hepsin, a recently identified prostate tumor marker that has been found to be selectively upregulated in high grade PIN and in primary prostate cancers. Because the tissue corresponding to the print micro-peels is undamaged by print collection, we are able to perform a detailed bistopathological review to assess the distribution and stage of tumor in each specimen. We found that the ratio of choline kinase to hepsin mRNA increased sharply with tumor grade, with an approximately 10 fold increase choline kinase/hepsin mRNA in Gleason 7 (4+3) as compared with Gleason 6 (3+3) prostate cancers. This finding corresponds with published observations that the intensity of the MRS choline resonance is correlated with the Gleason grade of a prostate tumor. We hypothesize that these 2 findings-the increased MRS choline peak in malignant areas of the prostate gland and the co-localization of choline kinase and hepsin upregulation - reflect the same clinically relevant processes. Using clinical cases and corresponding radical prostatectomy specimens, we propose to map the tissue/tumor expression profiles of a set of genes in the choline metabolic pathway and compare these profiles to the in vivo prostate MRI/MRS spectra, to the tissue histopathology and to the "signatures" of tumor markers proposed to be predictors of prostate cancer aggressiveness. We hypothesize that the gene expression profiles of the choline metabolic pathways will differentiate prostate cancer subtypes and differentiate malignancy from non- malignant MRS mimics of prostate cancer. These choline pathway expression profiles also provide the foundation for new clinical strategies in which selective inhibitors may improve the discrimination of MRI/MRS, permitting greater utilization of these techniques in the non-invasive assessment of prostate cancer and non-malignant prostate lesions.

描述（由申请人提供）：磁共振波谱 (MRS) 与磁共振成像 (MRI) 相结合是一种快速发展的无创技术，目前正在评估其作为确定临床器官受限患者前列腺癌位置、分期和分级的工具疾病。前列腺恶性区域的 MRS 谱的代谢变化特征包括胆碱增加和柠檬酸盐峰值减少。有人提出胆碱峰升高反映了肿瘤相关细胞膜的合成，磷脂酰胆碱的从头形成增加。然而，人们对前列腺癌中观察到的胆碱光谱背后的基因表达变化知之甚少。我们更大项目的主要目标是确定与 MRI/MRS 可检测前列腺癌相对应的分子事件。该提案中概述的项目的目标是表征前列腺癌中 MRS 可检测胆碱增加背后的基因表达变化。在初步研究中，我们绘制了从含有格里森 6,7 级或8 前列腺癌。胆碱激酶的表达模式与 hepsin 的表达模式密切相关，hepsin 是一种最近发现的前列腺肿瘤标志物，已被发现在高级别 PIN 和原发性前列腺癌中选择性上调。由于与打印微剥离相对应的组织不会因打印收集而受损，因此我们能够进行详细的双病理学检查，以评估每个标本中肿瘤的分布和阶段。我们发现，胆碱激酶与 hepsin mRNA 的比率随着肿瘤分级而急剧增加，与 Gleason 6 (3+3) 前列腺癌相比，Gleason 7 (4+3) 中胆碱激酶/hepsin mRNA 增加了约 10 倍。这一发现与已发表的观察结果一致，即 MRS 胆碱共振的强度与前列腺肿瘤的格里森分级相关。我们假设这两个发现——前列腺恶性区域的 MRS 胆碱峰值增加以及胆碱激酶和 hepsin 上调的共定位——反映了相同的临床相关过程。使用临床病例和相应的根治性前列腺切除术标本，我们建议绘制胆碱代谢途径中一组基因的组织/肿瘤表达谱，并将这些谱与体内前列腺 MRI/MRS 光谱、组织病理学和组织病理学进行比较。肿瘤标志物的“特征”被认为是前列腺癌侵袭性的预测因子。我们假设胆碱代谢途径的基因表达谱将区分前列腺癌亚型，并将恶性肿瘤与前列腺癌的非恶性 MRS 模拟区分开来。这些胆碱途径表达谱还为新的临床策略提供了基础，其中选择性抑制剂可以改善 MRI/MRS 的辨别力，从而允许在前列腺癌和非恶性前列腺病变的非侵入性评估中更多地利用这些技术。