Prosaposin, a novel tumor marker for prostate cancer

描述(申请人提供)：需要识别仅在恶性状态下高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)的诊断和治疗水平。我们从分化较差的雄激素非依赖性前列腺癌细胞系PC-3中克隆了丙皂苷。到目前为止，我们的结果显示：1)转移性前列腺癌组织中丙皂苷的表达高于雄激素依赖(AD)的前列腺癌细胞，2)激素不敏感的前列腺癌患者血清中的丙皂苷水平高于正常男性人群，3)前列腺癌细胞和前列腺癌移植瘤和转移淋巴结的活检标本中扩增了丙皂苷基因，4)丙皂苷刺激AD和Al前列腺癌细胞的生长、迁移和侵袭，并作为细胞存活和抗凋亡因子。这些结果使我们提出了丙皂苷参与前列腺癌发生的假说，并具有前列腺癌标记物的特征。因此，该项目的目标是确定该分子作为前列腺癌肿瘤标记物的有用性。本R21计划的具体目标是：1.评估前列腺癌组织中增殖的肿瘤细胞中丙皂甙的表达与患者Gleason‘s评分和血清PSA水平的关系。我们将利用免疫组织化学染色和组织芯片技术检测增殖中(Ki-67阳性)肿瘤细胞中丙皂甙的表达水平及其与当前最重要的两个预测因子Gleason评分(GS)和PSA的关系。2.探讨前列腺癌组织中异丙皂苷表达作为分化或疾病进展指标的临床意义。利用灵敏的激光捕获显微切割、实时定量聚合酶链式反应和DELFIA-丙皂苷免疫定量分析，我们将：a)在前列腺癌根治术标本的冰冻组织切片中，评估丙皂苷(mRNA和蛋白)表达与主要Gleason‘s模式(作为腺体分化的指标)之间的相关性；以及b)在患者血清中，评估丙皂苷与转移性和非转移性前列腺癌、激素敏感和激素难治性以及其他预后或风险因素(如PSA、GS、年龄、种族)的关系。这一探索性(R21)项目的结果将为未来大型前瞻性临床研究的设计提供基础，该研究将测试丙皂苷作为肿瘤标记物的有效性、可靠性和可预测性，以及与前列腺癌严重程度、进展、治疗反应和结果的关系。

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.