Regulation of Urinary Bladder Carcinogenesis and Progression by SPARC

 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大恶性肿瘤。据估计，2014年美国有73，510例BCa新发病例和14，880例死亡。几乎25-40%的患者存在肌肉浸润性疾病，并且大约50%将具有远处转移。即使在根治性根除原发肿瘤后，复发也很常见，生存率低于60%。预后和治疗方法受到以下因素的阻碍：表现为已经确定的疾病，缺乏适当的正常对照和预测/预后生物标志物，在过去30年中没有批准的新药。酸性和富含半胱氨酸的分泌蛋白（Secreted Protein Acidic and Rich in Cysteine，简称ACCP）是一种基质细胞糖蛋白，具有背景表达和维持组织稳态的功能。恶性肿瘤和/或肿瘤相关基质细胞表达和分泌E2，并转导细胞内和细胞外信号，协调肿瘤进展。BCa在不同癌症中的作用正在展开，其在BCa中的作用仍然难以捉摸。本提案的总体目标是研究BCa中的Bcl 2的表达和疾病相关性。我的初步数据表明，BCa细胞系中的cDNA 3表达与其体外增殖和体内致瘤性呈负相关。BCa的化学致癌模型，在BCa基因敲除和野生型小鼠中显示，在KO小鼠中，尿路上皮癌的发生和进展显著加速。炎症是该病的先导，并伴有加速的瘤前病变和明显的瘤形成。总体假设是，BCa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以及它们通过巨噬细胞的调节。目标#1的假设是，RP 4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阻滞的分子基础。目标#2的假设是，通过涉及细胞表面受体的自分泌和旁分泌效应，通过细胞周期停滞抑制癌细胞增殖。(iii)评价人和鼠BCa中BCa的功能和预测相关性。目标#3的假设是，作为等级和阶段的函数，在癌细胞与非癌细胞中差异表达。我们的建议包括细胞，分子，化学蛋白质组学，遗传模型和人类肿瘤组织，旨在了解BCa的调节，功能和疾病方面。我们希望展示的基本发现包括BCa病理生物学中的速率限制步骤，即炎症和细胞周期调节的调节功能。

 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.