Prostate MRI and MRS: Correlations with Gene Expression

描述（由申请人提供）：磁共振波谱（MRS）结合磁共振成像（MRI）是一种快速发展的无创技术，正在评估作为临床器官局限性疾病患者确定前列腺癌位置、分期和分级的工具。前列腺恶性区MRS谱的代谢变化特征包括胆碱升高和柠檬酸盐峰降低。有人提出，升高的胆碱峰反映了肿瘤相关的细胞膜合成，磷脂酰胆碱的新生形成增加。然而，人们对前列腺癌中胆碱谱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。本提案中概述的项目目标是表征前列腺癌中MRS可检测胆碱增加的基因表达变化。在初步研究中，我们在包含Gleason分级6、7或8级前列腺癌根治性前列腺切除术标本中获得的组织打印微皮中绘制了胆碱激酶（可能是含胆碱膜脂从头合成途径中的第一种调节酶）的表达图谱。胆碱激酶的表达模式与肝素的表达模式密切相关，肝素是一种最近发现的前列腺肿瘤标志物，在高级别PIN和原发性前列腺癌中被发现选择性上调。由于与打印微剥离相对应的组织未被打印收集损坏，因此我们能够进行详细的生物病理学检查，以评估每个标本中肿瘤的分布和分期。我们发现胆碱激酶与hepsin mRNA的比值随着肿瘤分级而急剧增加，与Gleason 7（4+3）前列腺癌相比，Gleason 6（3+3）前列腺癌中胆碱激酶/hepsin mRNA的比值大约增加了10倍。这一发现与已发表的观察结果一致，即MRS胆碱共振强度与前列腺肿瘤的Gleason分级相关。我们假设这两个发现——前列腺恶性区域MRS胆碱峰的增加以及胆碱激酶和肝素上调的共定位——反映了相同的临床相关过程。利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谱、组织组织病理学和被认为是前列腺癌侵袭性预测因子的肿瘤标志物的“特征”进行比较。我们假设胆碱代谢途径的基因表达谱可以区分前列腺癌亚型，并区分恶性和非恶性的前列腺癌MRS模拟物。这些胆碱通路表达谱也为新的临床策略提供了基础，其中选择性抑制剂可以提高MRI/MRS的区分，允许这些技术在前列腺癌和非恶性前列腺病变的非侵入性评估中得到更多的利用。

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.