Regulation of Urinary Bladder Carcinogenesis and Progression by SPARC

SPARC 对膀胱癌发生和进展的调节

• 批准号: 9030559
• 负责人: Neveen Said
• 金额: $ 35.46万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-11 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9030559
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Atypia; Bioinformatics; Biological Markers; Bladder; Cancer cell line; Cancerous; Carcinogens; Cell Cycle Arrest; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell Surface Receptors; Cells; Cessation of life; Chemicals; Cyclins; Cysteine; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Distant Metastasis; Dysplasia; Exhibits; Exposure to; Gene Expression Profiling; Genetic Models; Genetic Transcription; Genitourinary system; Glycoproteins; Goals; Growth; Health; Homeostasis; Human; In Vitro; Incidence; Infiltration; Inflammation; Knock-out; Knockout Mice; Knowledge; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Modeling; Molecular; Mus; Muscle; Natural History; Neoplasms; Oxidative Stress; Pathway interactions; Patients; Play; Pre-Clinical Model; Primary Neoplasm; Prognostic Marker; Proteins; Proteomics; Reactive Oxygen Species; Recurrence; Regulation; Role; S Phase; Signal Transduction; Staging; Stromal Cells; Survival Rate; System; Therapeutic; Tissues; Tobacco use; Transcription Factor AP-1; Tumor Suppressor Proteins; Tumor Tissue; Tumorigenicity; United States; Wild Type Mouse; autocrine; base; cancer cell; cancer initiation; carcinogenesis; chemical carcinogenesis; chemoproteomics; clinically relevant; diagnostic biomarker; differential expression; effective therapy; extracellular; genetic signature; in vivo; inhibitor/antagonist; insight; macrophage; neoplastic cell; novel; novel therapeutics; outcome forecast; paracrine; personalized medicine; prognostic; proteomic signature; public health relevance; three dimensional cell culture; tobacco exposure; tumor; tumor microenvironment; tumor progression

 DESCRIPTION (provided by applicant): Bladder cancer (BCa) is the fourth malignancy affecting the genitourinary system in United States. With estimated, 73,510 new cases and 14,880 deaths from BCa in 2014 in The United States. Almost 25-40% of patients present with muscle invasive disease, and approximately 50% will harbor distant metastases. Even after radical eradication of the primary tumor, recurrence is common and survival rates are less than 60%. Prognostic and therapeutic approaches are hampered by presentation with an already established disease, lack of appropriate normal controls and predictive/prognostic biomarkers with no approved new drugs in the past 30 years. Secreted Protein Acidic and Rich in Cysteine (SPARC) is a matricellular glycoprotein that exhibits contextual expression and functions maintaining tissue homeostasis. SPARC is expressed and secreted by malignant and/or tumor-associated stromal cells and transduces intra and extracellular signals, orchestrating tumor progression. The role of SPARC in different cancers is unfolding and its role in BCa is still elusive. The overall goal of this proposal is to investigate the expression and disease association of SPARC in BCa. My preliminary data show that SPARC expression in BCa cell lines was negatively associated with their in vitro proliferation and in vivo tumorigenicity. Chemical-carcinogenesis model of BCa, in SPARC knockout and wild-type mice showed that urothelial carcinogenesis and progression were significantly accelerated in KO mice. Inflammation is the forerunner of the disease and was accompanied by accelerated preneoplasia and overt neoplasia. The overall hypothesis is that SPARC exhibits differential expression and functions in BCa microenvironment. Our specific aims are: (i) Characterize the interactions between cancer cells and macrophages and their regulation by SPARC. The hypothesis for Aim#1 is that SPARC plays an important anti-inflammatory role regulating cancer cell-macrophage crosstalk. (ii) Define the molecular basis for SPARC-mediated cell cycle arrest of bladder cancer cells. The hypothesis for Aim#2 is that SPARC restrain cancer cell proliferation through cell cycle arrest through autocrine and paracrine effects involving cell surface receptor(s). (iii) Evaluate the functional and predictive relevance of SPARC in human and murine BCa. The hypothesis for Aim#3 is that SPARC is differentially expressed in cancerous versus non-cancerous cells as a function of grade and stage. Our proposal includes cell, molecular, chemoproteomic, genetic models and human tumor tissues aimed at understanding the regulation, function and disease aspects of SPARC in BCa. Fundamental findings that we hope to show include a function for SPARC regulating the rate limiting steps in BCa pathobiology, namely inflammation and cell cycle regulation.

 描述（由申请人提供）：膀胱癌（BCa）是影响美国泌尿生殖系统的第四种恶性肿瘤。据估计，2014 年美国有 73,510 例 BCa 新发病例和 14,880 例死亡。近 25-40% 的患者出现肌肉侵袭性疾病，约 50% 会出现远处转移。即使根治原发肿瘤后，复发也很常见，生存率低于60%。预后和治疗方法因已确定的疾病、缺乏适当的正常对照和预测/预后生物标志物以及过去 30 年来没有批准的新药而受到阻碍。富含半胱氨酸的酸性分泌蛋白 (SPARC) 是一种基质细胞糖蛋白，具有上下文表达和维持组织稳态的功能。 SPARC 由恶性和/或肿瘤相关基质细胞表达和分泌，并转导细胞内和细胞外信号，协调肿瘤进展。 SPARC 在不同癌症中的作用正在逐渐显现，但其在 BCa 中的作用仍然难以捉摸。该提案的总体目标是研究 SPARC 在 BCa 中的表达和疾病关联。我的初步数据表明，BCa 细胞系中的 SPARC 表达与其体外增殖和体内致瘤性呈负相关。 SPARC 敲除小鼠和野生型小鼠中的 BCa 化学致癌模型表明，KO 小鼠中尿路上皮癌的发生和进展显着加速。炎症是该疾病的先兆，并伴有加速的瘤形成前期和明显的瘤形成。总体假设是 SPARC 在 BCa 微环境中表现出差异表达和功能。我们的具体目标是： (i) 表征癌细胞和巨噬细胞之间的相互作用及其 SPARC 的调节。 Aim#1 的假设是 SPARC 在调节癌细胞-巨噬细胞串扰中发挥重要的抗炎作用。 (ii) 定义 SPARC 介导的膀胱癌细胞细胞周期停滞的分子基础。 Aim#2 的假设是 SPARC 通过涉及细胞表面受体的自分泌和旁分泌效应的细胞周期停滞来抑制癌细胞增殖。 (iii) 评估 SPARC 在人类和小鼠 BCa 中的功能和预测相关性。 Aim#3 的假设是，SPARC 在癌性细胞和非癌性细胞中的表达存在差异，且随级别和分期的变化而变化。我们的提案包括细胞、分子、化学蛋白质组学、遗传模型和人类肿瘤组织，旨在了解 SPARC 在 BCa 中的调节、功能和疾病方面。我们希望展示的基本发现包括 SPARC 调节 BCa 病理学限速步骤的功能，即炎症和细胞周期调节。