Prosaposin, a novel tumor marker for prostate cancer

描述（由申请人提供）：需要识别仅在恶性状态下大量表达并与疾病分期和进展相关的肿瘤标志物，以提高前列腺癌（PCa）的诊断和治疗。我们从低分化雄激素独立（Al） PCa细胞系PC-3中克隆了prosaposin。我们目前的研究结果显示：1)转移性前列腺癌中prosaposin的表达高于雄激素依赖性（AD）前列腺癌细胞，2)激素难愈性前列腺癌患者血清中prosaposin的水平高于正常男性，3)前列腺癌细胞和前列腺癌异种移植和转移性淋巴结活检标本中prosaposin基因扩增，4)prosaposin刺激生长、迁移和侵袭，并在AD和Al前列腺癌细胞中发挥细胞存活和抗凋亡因子的作用。这些结果使我们提出prosaposin参与前列腺癌发生的假设，并具有前列腺癌标志物的特征。因此，该项目的目标是确定该分子作为前列腺癌肿瘤标志物的有效性。R21项目的具体目标是：1。目的探讨前列腺癌组织增生肿瘤细胞中prosaposin表达与患者Gleason评分及血清psa水平的关系。我们将使用免疫组织化学染色和组织芯片来测量增殖（Ki-67阳性）肿瘤细胞中prosaposin的表达水平及其与两个最重要的当前预测因素Gleason评分（GS）和PSA的关系。2. 目的：探讨前列腺癌中前列腺素表达作为分化或疾病进展标志的临床意义。使用敏感的定量激光捕获显微解剖，实时荧光定量PCR和DELFIA-prosaposin免疫定量分析，我们将：a)在根治性前列腺切除术标本的冷冻组织切片中，评估prosaposin （mRNA和蛋白）表达与显性Gleason模式（作为腺体分化的衡量指标）之间的相关性；b)在患者血清中，评估prosaposin与转移性与非转移性前列腺癌、激素敏感型与激素难治性前列腺癌以及其他预后或危险因素（如PSA、GS、年龄、种族）之间的关系。这个探索性（R21）项目的结果将为设计未来大规模的前瞻性临床研究提供基础，这些研究将测试prosaposin作为肿瘤标志物与PCa严重程度、进展、治疗反应和结果之间的关系的有效性、可靠性和可预测性。

DESCRIPTION (provided by applicant): Identification of tumor markers that are expressed at high amounts only in malignant state and correlate with disease stage and progression are needed to improve the diagnosis and treatment of prostate cancer (PCa). We have cloned prosaposin from the poorly differentiated androgen-independent (Al) PCa cell line, PC-3. Our results to date show: 1) prosaposin expression is higher in metastatic Al than in androgen-dependent (AD) PCa cells, 2) serum levels of prosaposin is higher in hormone-refractory PCa patients than in the normal male population, 3) prosaposin gene is amplified in PCa cells and punch biopsy specimens of prostate cancer xenografts and metastatic lymph nodes, and 4) prosaposin stimulates growth, migration, and invasion and acts as a cell survival and anti-apoptotic factor in both AD and Al PCa cells. These results lead us to propose the hypothesis that prosaposin contributes to prostate carcinogenesis and has the characteristics of a PCa tumor marker. Thus, the goal of this project is to establish the usefulness of this molecule as a tumor marker for prostate cancer. The Specific Aims of this R21 project are: 1. To assess, in proliferating tumor cells from prostate cancer tissues, the relationship between prosaposin expression and patients' Gleason's score and serum-PSA level. We will use immunohistochemical staining and tissue microarray to measure prosaposin expression level in proliferating (Ki-67 positive) tumor cells and its relationship with the two most important current predictive factors, Gleason's score (GS) and PSA. 2. To define the clinical significance of prosaposin expression as a marker of differentiation or disease progression in prostate cancer. Using sensitive quantitative laser capture microdissection, Real-Time PCR, and DELFIA-prosaposin immunoquantification assays, we will: a) in frozen tissue sections of radical prostatectomy specimens, assess the correlation between prosaposin (mRNA and protein) expression and dominant Gleason's pattern (as a measure of glandular differentiation), and b) in sera from patients, evaluate the relationship between prosaposin and metastatic versus non-metastatic PCa, hormone-sensitive versus hormone-refractory, and other prognostic or risk factors (e.g., PSA, GS, age, race) Significance. The results of this exploratory (R21) project will provide the basis for design of future large- scale prospective clinical investigation that will test the validity, reliability, and predictability of prosaposin as a tumor marker in relationship to PCa severity, progression, response to treatment, and outcomes.