Mechanisms of Pancreatic Cancer Inhibition by SPARC

SPARC 抑制胰腺癌的机制

基本信息

批准号：
8584190
负责人：
SUSAN L. COHN
金额：
$ 20.62万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8584190
关键词：
Adenocarcinoma Cell Angiogenic Peptides Animal Model Binding Cancer Etiology Cells Cessation of life Chemotherapy-Oncologic Procedure Co-Immunoprecipitations Complex Country Cysteine Data Desmoplastic Development Diagnosis Diazomethane Disease Down-Regulation Drug Delivery Systems Drug resistance Enzymes Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Follistatin Goals Growth Growth Factor Human Immune Length Life Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Maps Mediating Molecular Chaperones Mus Neoplasms Operative Surgical Procedures Pancreas Pancreatic Ductal Adenocarcinoma Patients Peptide Mapping Peptides Pharmaceutical Preparations Play Precipitation Property Protein Binding Proteins Recombinant Proteins Resistance Role Site Staging Structure Surface Technology Testing Tumor Suppression Tumor Suppressor Proteins Tumor Tissue Xenograft Model alternative treatment angiogenesis base cancer type conventional therapy crosslink cytokine effective therapy extracellular insight malignant breast neoplasm mortality new therapeutic target novel novel therapeutics pancreatic cancer cells pancreatic neoplasm preclinical study public health relevance response small hairpin RNA tandem mass spectrometry therapeutic target treatment strategy tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most aggressive human malignancies. In most patients it is diagnosed at advanced stages not amenable by surgery, and it is highly resistant to conventional treatments. With median survival less than 1 year and 5-year survival less than 5%1, the need for additional treatment strategies is high. Severe desmoplasia is a hallmark of pancreatic cancer, and the tumor microenvironment has been shown to play an essential role in the progression and chemoresistance of this disease. Thus, the tumor microenvironment is a promising therapeutic target for pancreatic cancer. Secreted Protein Acidic and Rich in Cysteine (SPARC) is a matricellular protein that modulates interactions between cells and their environment2,3. We have shown that SPARC modifies the assembly and organization of the extracellular matrix4 by functioning as an extracellular chaperone5. Our studies have demonstrated that SPARC inhibits the growth of several types of cancers (6,7 and Preliminary Studies). We have established that the anti-tumor properties of SPARC are mediated in part, by its angiogenesis inhibition6 and by blockade of fibroblast activation4, two major features of cancer-induced desmoplasia. Using structure-functional studies, we have shown that SPARC peptides corresponding to the highly conserved follistatin domain have potent anti- angiogenic activity8,9 and inhibit the growth of neuroblastoma9, pancreatic, lung, and breast cancers (Preliminary Studies). Thus SPARC has tumor suppressor functions in a broad range of neoplasms. Based on these data, we hypothesize that by interacting with matrix and stromal proteins, SPARC inhibits the growth of pancreatic cancer by blocking desmoplastic changes, and creating a more "normal" microenvironment that is non-permissive for tumor growth. The mechanisms by which SPARC modulates the tumor microenvironment and inhibits tumor growth remain largely unknown. We propose elucidating the mechanism using a unique systematic approach, developed by Dr. He, the co-PI on this grant10-12, to isolate proteins that are targeted by SPARC in pancreatic tumor tissue. Established interactions will be validated by co-expression and co-precipitation with SPARC. The functional significance of validated targets will be tested by down-regulation with shRNA and the ability to counteract anti-tumor properties of SPARC in a mouse xenograft model.

描述（由申请人提供）：胰腺癌是人类最具侵略性的恶性肿瘤之一。在大多数患者中，它在晚期阶段被诊断出来不受手术的诊断，并且对常规治疗具有很高的抵抗力。由于中位生存期少于1年，而5年生存率小于5％1，因此对其他治疗策略的需求很高。严重的脱木质是胰腺癌的标志，肿瘤微环境已被证明在该疾病的进展和化学上起着至关重要的作用。因此，肿瘤微环境是胰腺癌的有前途的治疗靶标。分泌的蛋白质酸性和富含半胱氨酸（SPARC）是一种基质蛋白，可调节细胞与其环境之间的相互作用2,3。我们已经表明，SPARC通过充当细胞外伴侣5来修饰细胞外矩阵4的组装和组织。我们的研究表明，SPARC抑制了几种类型的癌症的生长（6,7和初步研究）。我们已经确定，SPARC的抗肿瘤特性部分是由其血管生成抑制作用和封闭成纤维细胞激活的阻断，这是癌症诱导的脱发的两个主要特征。使用结构功能性研究，我们表明，与高度保守的卵泡蛋白结构域相对应的SPARC肽具有有效的抗血管生成活性8,9并抑制神经母细胞瘤9，胰腺，肺和乳腺癌的生长（前研究）。因此，SPARC具有在广泛的肿瘤中的肿瘤抑制作用。基于这些数据，我们假设通过与基质和基质蛋白相互作用，SPARC通过阻断脱糖性变化，并创造出更加“正常”的微环境，从而抑制胰腺癌的生长，而这种微环境对肿瘤的生长无可或要。 SPARC调节肿瘤微环境并抑制肿瘤生长的机制在很大程度上尚不清楚。我们提出了使用独特的系统方法阐明该机制，该方法是由该授予10-12的Co-Pi博士开发的，以分离由SPARC靶向胰腺肿瘤组织中的蛋白质。建立的相互作用将通过与SPARC共表达和共沉淀来验证。经过验证的目标的功能意义将通过SHRNA下调以及在小鼠异种移植模型中抵消SPARC的抗肿瘤特性的能力来测试。