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

Prosaposin：非裔美国人前列腺癌进展的新型生物标志物

基本信息

批准号：
8288659
负责人：
SHAHRIAR KOOCHEKPOUR
金额：
$ 41.41万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8288659
关键词：
Affect African American Aftercare Age Apoptotic Behavior Benign Biological Biological Assay Biological Markers Cancer Etiology Caucasians Caucasoid Race Cell Line Cell Survival Cells Cessation of life Characteristics Clinical Data Development Diagnosis Disease Disease Progression Early Diagnosis Enzyme-Linked Immunosorbent Assay Extracellular Matrix Gland Gleason Grade for Prostate Cancer Health Services Accessibility In Vitro Incidence Indolent Investigation Laboratories Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Metastatic Prostate Cancer Modeling Molecular NOD/SCID mouse Neoplasm Metastasis Nude Mice Organ PC3 cell line Patients Pattern Peptide Hydrolases Phenotype Pilot Projects Primary Neoplasm Prognostic Factor Prostate Proteins RNA Interference Radical Prostatectomy Risk Factors Sampling Screening for Prostate Cancer Screening procedure Serum Specimen Staging Staining method Stains TNM Testing Time Tissues Tumor Markers Undifferentiated Xenograft procedure base cancer cell cancer diagnosis cell motility clinically significant follow-up implantation improved mRNA Expression men migration mortality novel overexpression prognostic protein expression racial difference subcutaneous tissue resource tumor tumor growth tumor progression tumor xenograft

项目摘要

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.

前列腺癌 (PCa) 是美国男性癌症相关死亡的第二大原因，是最严重的癌症非裔美国人任何恶性疾病的种族差异，发病率高出 1.6-1.9 倍，且发病率高出 2- 死亡率比白人高3倍。非裔美国人的 PCa 呈现出更先进的临床特征阶段和侵袭性肿瘤。需要 PCa 生物标志物来改善具有临床意义的早期检测肿瘤并区分惰性或缓慢生长的肿瘤与更具侵袭性的肿瘤。在我们寻找肿瘤的过程中标记物，我们将前塞塞辛（PSAP）克隆为一种分泌蛋白，并发现其在转移性肿瘤中过度表达 PCa 细胞和组织。之前，我们证明了 PSAP 和/或其活性分子衍生物可以增加迁移和侵袭并上调 PCa 细胞中基质降解蛋白水解酶的表达。在白种人中，与原发性前列腺癌或正常人相比，转移性前列腺癌的血清 PSAP 水平升高前列腺组织。此外，器官限制和器官限制之间的血清 PSAP 水平没有差异。局部侵袭性肿瘤。与白种人相比，我们对非裔美国人的试点研究表明：a) PSAP 的表达在具有 Gleason 4/5 级模式的未分化肿瘤中显着高于在格里森 d 3 级分化肿瘤或良性腺体 (BPH) 和 b) 血清 PSAP 水平较高局部侵袭性（III/IV 期）肿瘤高于器官局限性（I/II 期）肿瘤，两者呈正相关随着疾病的进展。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和非侵袭性肿瘤的新型生物标志物的特征非裔美国患者具有攻击性。为了检验我们的假设，我们提出以下目标：1）定义血清 PSAP 作为非洲 PCa 进展或侵袭性标志物的临床意义美国人； 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 PCa 进展或攻击性的预测因素或预后因素； 3) 确定 PSAP 与 PSAP 过表达或沉默的侵袭性和转移性表型之间的关联非洲裔美国人 PCa 细胞。我们将使用免疫组织化学分析和夹心 ELISA 分析来量化大量组织和血清样本中的 PSAP 表达水平并确定其与 PCa 侵袭性和进展的临床组织病理学预测因子或预后因子的关联在非裔美国人中。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发生率和自发转移能力衍生的 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/或攻击性生物标志物的重要性可以进一步用于临床开发。