Prosaposin, a novel tumor marker for prostate cancer

描述（由申请人提供）：需要鉴定仅在恶性状态下以高量表达并与疾病阶段和进展相关的肿瘤标志物，以改善前列腺癌（PCa）的诊断和治疗。我们已经从低分化的雄激素非依赖性（Al）PCa细胞系PC-3中克隆了鞘脂激活蛋白原。我们迄今为止的结果显示：1）在转移性A1中的鞘脂激活蛋白原表达高于雄激素依赖性（AD）PCa细胞，2）在难治性PCa患者中的鞘脂激活蛋白原血清水平高于正常男性群体，3）鞘脂激活蛋白原基因在PCa细胞和前列腺癌异种移植物和转移性淋巴结的穿刺活检样本中扩增，和4）鞘脂激活蛋白原刺激生长、迁移，并在AD和AlPCa细胞中作为细胞存活和抗凋亡因子。这些结果使我们提出了这样的假设，即鞘脂激活蛋白原有助于前列腺癌的发生，并具有前列腺癌肿瘤标志物的特征。因此，该项目的目标是建立这种分子作为前列腺癌肿瘤标志物的有用性。R21项目的具体目标是：1。评估前列腺癌组织中增殖肿瘤细胞中saposin原表达与患者Gleason评分和血清PSA水平之间的关系。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）肿瘤细胞中的鞘脂激活蛋白原表达水平及其与目前最重要的两个预测因子Gleason评分（GS）和PSA的关系。2.明确鞘脂激活蛋白原表达作为前列腺癌分化或疾病进展标志物的临床意义。使用灵敏的定量激光捕获显微切割、实时PCR和DELFIA-Prosaposin免疫定量测定，我们将：a）在根治性前列腺切除术标本的冷冻组织切片中，评估前鞘脂酶与前列腺素之间的相关性，（mRNA和蛋白质）表达和显性Gleason模式（作为腺分化的量度），和B）在来自患者的血清中，评估鞘脂激活蛋白原与转移性与非转移性PCa、肿瘤敏感性与肿瘤难治性之间的关系，以及其他预后或风险因素（例如，PSA、GS、年龄、种族）显著性。该探索性（R21）项目的结果将为未来大规模前瞻性临床研究的设计提供基础，该研究将检测鞘脂激活蛋白原作为肿瘤标志物与PCa严重程度、进展、治疗反应和结局的关系的有效性、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.