Prostate MRI and MRS: Correlations with Gene Expression

描述(申请人提供)：磁共振波谱(MRS)结合核磁共振成像(MRI)是一种快速发展的非侵入性技术，正在评估中，作为确定临床器官受限疾病患者前列腺癌位置、分期和分级的工具。前列腺癌恶性区域的MRS谱特征是代谢改变，包括胆碱升高和柠檬酸盐峰降低。有人认为，升高的胆碱峰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，人们对前列腺癌胆碱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可检测到的前列腺癌相对应的分子事件。这项提案中概述的项目的目标是描述前列腺癌MRS可检测胆碱增加背后的基因表达变化。在初步研究中，我们对含有Gleason 6级、7级或8级前列腺癌的前列腺癌根治术标本的组织印迹微皮中胆碱激酶(第一个也可能是含膜脂胆碱从头合成途径中的调节酶)的表达进行了定位。胆碱激酶的表达模式与最近发现的前列腺癌标志物肝素密切相关，肝素被发现在高级别PIN和原发性前列腺癌中选择性上调。由于印迹微皮对应的组织未受到印迹收集的破坏，我们能够进行详细的双病理检查，以评估每个标本中肿瘤的分布和分期。Gleason 7(4+3)前列腺癌与Gleason 6(3+3)前列腺癌相比，胆碱激酶/肝素mRNA比值增加了近10倍。这一发现与发表的观察结果一致，即MRS胆碱共振的强度与前列腺癌的Gleason分级相关。我们假设这两个发现-前列腺癌恶性区域MRS胆碱峰的增加以及胆碱激酶和肝素上调的共同定位-反映了相同的临床相关过程。利用临床病例和相应的前列腺癌根治术标本，我们建议绘制胆碱代谢途径中一组基因的组织/肿瘤表达图谱，并将这些图谱与体内前列腺癌MRI/MRS谱、组织病理学和被认为是前列腺癌侵袭性预测指标的肿瘤标志物进行比较。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，并区分前列腺癌的恶性和非恶性MRS模拟。这些胆碱途径的表达谱也为新的临床策略提供了基础，在这些策略中，选择性抑制剂可以提高MRI/MRS的识别率，从而使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应用。

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.