Prosaposin: A Novel Biomarker of Prostate Cancer Progression in African Americans

前列腺癌（PCa）是美国男性癌症相关死亡的第二大原因， 非裔美国人中任何恶性疾病的种族差异，发病率高1.6-1.9倍， 死亡率是白种人的3倍。非裔美国人的PCa表现出更严重的临床 阶段和侵袭性肿瘤。需要PCa生物标志物来改善临床显著性前列腺癌的早期检测。 肿瘤和区分惰性或缓慢生长的肿瘤更具侵略性。在寻找肿瘤的过程中 标记，我们克隆了鞘脂激活蛋白原（PSAP）作为一种分泌蛋白，并发现其在转移性乳腺癌中的过度表达。 PCa细胞和组织。以前，我们证明了PSAP和/或其活性分子衍生物增加了 迁移和侵袭，并上调PCa细胞中基质降解蛋白水解酶的表达。在 高加索人，与原发性PCa或正常人相比，转移性PCa的血清PSAP水平升高 前列腺组织此外，在器官限制组和非器官限制组之间， 局部侵袭性肿瘤与高加索人相比，我们在非裔美国人中的初步研究表明：a）组织 PSAP在Gleason分级4/5型未分化肿瘤中的表达显著高于在Gleason分级4/5型未分化肿瘤中的表达。 Gleason分级为d 3或良性腺体（BPH）的分化型肿瘤和B）血清PSAP水平高于 局部浸润性（III/IV期）肿瘤比器官局限性（I/II期）肿瘤， 疾病进展。基于这些观察，我们假设PSAP有助于PCa 进展，并具有区分侵袭性肿瘤与非侵袭性肿瘤的新生物标志物的特征。 非裔美国人的攻击性为了验证我们的假设，我们提出了以下目标：1）定义 血清PSAP作为非洲人前列腺癌进展或侵袭性标志物的临床意义 2）确定PSAP的组织表达与临床和组织病理学之间的关联 非裔美国人中PCa进展或攻击性的预测因子或指示因子;以及3）确定 PSAP与PSAP过表达或沉默患者侵袭性和转移性表型之间的关系 非洲裔美国人PCa细胞。我们将使用免疫组织化学分析和ELISA检测， 定量大量组织和血清样品中的PSAP表达水平， 与PCa侵袭性和进展的临床组织病理学预测因子或预测因子相关 在非裔美国人中。我们还将测试PSAP表达增加或减少对肿瘤生长的影响。 非裔美国人皮下和原位肿瘤异种移植物的自发转移率和自发转移能力- PCa细胞。在本提案结束时，我们将定义临床和组织病理学 PSAP作为非裔美国人PCa进展和/或侵袭性生物标志物的意义， 可以进一步用于临床开发。

Prostate cancer (PCa), the second leading cause of cancer-related death in US men, presents the greatest racial disparity of any malignant disease in African Americans, with a 1.6-1.9 times higher incidence rate and 2- 3 times higher mortality rate than Caucasians. PCa in African Americans presents with more advanced clinical stages and aggressive tumors. PCa biomarkers are needed to improve early detection of clinically significant tumors and to distinguish indolent or slow growing tumors from more aggressive ones. In our search for tumor markers, we cloned prosaposin (PSAP) as a secreted protein and discovered its overexpression in metastatic PCa cells and tissues. Previously, we demonstrated that PSAP and/or its active molecular derivatives increase migration and invasion and upregulate matrix-degrading proteolytic enzymes expression in PCa cells. In Caucasians, serum-PSAP levels are increased in metastatic PCa when compared to primary PCa or normal prostate tissues. In addition, there was no difference in serum-PSAP levels between organ-confined and locally-invasive tumors. In contrast to Caucasians, our pilot study in African Americans shows that a) tissue expression of PSAP is significantly higher in undifferentiated tumors with Gleason grade 4/5 pattern than in the differentiated tumors with Gleason grade d 3 or benign glands (BPH) and b) serum-PSAP levels are higher in locally invasive (stage III/IV) tumors than in the organ-confined (stage I/II) tumors which positively correlates with disease progression. Based on these observations, we hypothesized that PSAP contributes to PCa progression and has the characteristics of a novel biomarker discriminating the aggressive tumors from non- aggressive ones in African American patients. To test our hypothesis, we propose the following Aims: 1) Define the clinical significance of serum-PSAP as a marker of PCa progression or aggressiveness in African Americans; 2) Determine the association between tissue expression of PSAP and clinical and histopathological predictors or prognosticators of PCa progression or aggressiveness in African Americans; and 3) Determine the association between PSAP and invasive and metastatic phenotypes in PSAP-overexpressed or -silenced African American PCa cells. We will use immunohistochemical analysis and sandwich-ELISA assays to quantify PSAP expression levels in a large pool of tissue and serum samples and to determine their association with clinicohistopathological predictors or prognosticators of PCa aggressiveness and progression in African Americans. We will also test the effect of increased or decreased PSAP expression on tumor growth rate and spontaneous metastatic ability in subcutaneous and orthotopic tumor xenografts in African American- derived PCa cells. At the conclusion of this proposal, we will have defined the clinical and histopathological significance of PSAP as a biomarker of PCa progression and/or aggressiveness in African Americans that could be further utilized in clinical development.