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

描述(申请人提供)：前列腺癌(PCa)是美国男性癌症相关死亡的第二大原因，在非裔美国人中呈现出最大的种族差异，发病率是白人的1.6-1.9倍，死亡率是高加索人的2-3倍。非裔美国人的前列腺癌具有更晚期的临床分期和侵袭性肿瘤。需要PCA生物标记物来改进对临床上有意义的肿瘤的早期检测，并将惰性或生长缓慢的肿瘤与更具侵袭性的肿瘤区分开来。在寻找肿瘤标记物的过程中，我们克隆了一种分泌型蛋白--丙皂苷(PSAP)，并发现其在转移的PCa细胞和组织中过表达。在此之前，我们证明了PSAP和/或其活性分子衍生物增加了前列腺癌细胞的迁移和侵袭，并上调了基质降解蛋白水解酶的表达。在高加索人中，与原发前列腺癌或正常前列腺组织相比，转移性前列腺癌患者的血清PSAP水平升高。此外，在器官受限肿瘤和局部侵袭性肿瘤之间，血清PSAP水平没有差异。与高加索人相比，我们在非裔美国人中的初步研究表明，a)Gleason分级4/5的未分化肿瘤中PSAP的组织表达显著高于Gleason分级d 3或良性腺体(BPH)的分化型肿瘤，以及b)局部侵袭性(III/IV期)肿瘤的血清PSAP水平高于器官受限(I/II期)肿瘤，这与疾病进展呈正相关。基于这些观察，我们假设PSAP有助于PCa的进展，并具有区分非裔美国人患者侵袭性和非侵袭性肿瘤的新生物标志物的特征。为了验证我们的假设，我们提出了以下目标：1)确定血清-PSAP作为非裔美国人前列腺癌进展或侵袭性标志的临床意义；2)确定PSAP组织表达与非裔美国人前列腺癌进展或侵袭性的临床和组织病理学预测或预测因素之间的关联；以及3)确定PSAP与PSAP过度表达或沉默的非裔美国人PCA细胞中侵袭和转移表型的相关性。我们将使用免疫组织化学分析和夹心ELISA法来量化大量组织和血清样本中PSAP的表达水平，并确定它们与非裔美国人PCa侵袭性和进展性的临床组织病理学预测因素或预测因素的相关性。我们还将测试PSAP表达的增加或减少对非裔美国人来源的PCa细胞皮下和原位移植瘤的肿瘤生长速度和自发转移能力的影响。在这项提案的结论中，我们将定义PSAP的临床和组织病理学意义，作为非裔美国人PCa进展和/或侵袭性的生物标记物，可以进一步用于临床开发。 公共卫生相关性：非裔美国人(AA)男性前列腺癌(PCA)的发病率、死亡率和侵袭性高于高加索人。为了提高对临床有意义的肿瘤的早期发现，并区分惰性或生长缓慢的肿瘤与更具侵袭性的肿瘤，需要可靠的预后因素或生物标记物。对我们初步发现的在局部侵袭性和/或转移性前列腺癌细胞、组织和血清样本中高水平表达丙皂苷(PSAP)的深入研究将为我们提供该分子作为前列腺癌筛查、诊断或治疗后随访的生物标记物的临床和组织病理学价值。

DESCRIPTION (provided by applicant): 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 up regulate 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-over expressed 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. PUBLIC HEALTH RELEVANCE: The incidences, mortality, and aggressiveness of prostate cancer (PCa) in African American (AA) men are higher than in Caucasians. To improve early detection of clinically significant tumors and to discriminate indolent or slow growing tumors from more aggressive ones, reliable prognostic factors or biomarkers are needed. An in-depth investigation of our preliminary discovery of a high expression of prosaposin (PSAP) levels in locally invasive and/or metastatic PCa cells, tissues, and serum samples from AA men would provide us with the clinical and histopathological values of this molecule as a biomarker for PCa screenings, diagnoses, or post-treatment follow up in AAs.