Defining mechanisms of extracellular communication for cancer therapy

定义癌症治疗的细胞外通讯机制

基本信息

批准号：
8623107
负责人：
ERWIN G VAN MEIR
金额：
$ 31.4万
依托单位：
EMORY UNIVERSITY
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：
2013-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8623107
关键词：
Adult Agonist Animal Lectins Animal Model Animals Apoptosis Apoptotic BH3 Domain Binding Binding Proteins Biodistribution Brain Neoplasms Bystander Effect C-terminal Carbohydrates Caspase Cell Culture Techniques Cell Death Cell Death Signaling Process Cell Surface Receptors Cell surface Cells Cessation of life Characteristics Clinical Communication Complex DNA Damage Data Development Disease Dose Elements Ensure Equilibrium Experimental Models Family Galactose Galactose Binding Lectin Galactosides Galectin 3 Genes Genetic Engineering Glioblastoma Glioma Growth Health Histology Human Implant In Vitro Integrins Knowledge Laboratories Lead Lectin Length Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Measures Mediating Modality Modeling Molecular Mus Mutation Normal Cell Nude Mice Outcome Pathway interactions Patients Polysaccharides Post-Translational Protein Processing Predisposition Process Protein p53 Proteins Public Health Radiation therapy Radiosurgery Reagent Research Role Schedule Signal Pathway Signal Transduction Survival Rate System Testing Therapeutic Therapeutic Agents Therapeutic Effect Tissues Toxic effect Translations Work anti-cancer therapeutic base cancer cell cancer therapy caspase-9 cell growth cell killing chemotherapy experience extracellular glycosylation in vivo inhibitor/antagonist innovation insight killings neoplastic cell novel novel therapeutics peptidomimetics prevent public health relevance receptor research study small molecule tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cancer is a major health problem worldwide and new therapies are critically needed, especially for glioblastoma the most fatal brain tumor. Unpublished studies in our lab have revealed a new bystander effect for tumor suppressor p53. Upon activation by chemo- or radiation therapies p53 induces the death of adjacent tumor cells, while sparing normal cells. We discovered that the effecter mechanism relies upon the secretion of galectin-3, a ¿-galactose-recognizing lectin, which induces apoptosis. We also found that secreted galectin-3 reduced tumor formation in vivo. In this proposal we will extend these initial findings by dissecting the underlying mechanisms and determine whether Gal3 has clinical potential. We will determine the type of apoptotic signaling pathways activated in tumor cells by extracellular galectin-3 (Aim 1), whether secreted galectin-3 selectively binds to a specific cell surface receptor, with tumor-specific characteristics (Aim 2), and whether Gal-3 delivery can be used as a viable therapeutic for cancer using an in vivo mouse glioma model (Aim 3). Our working hypothesis is that p53 exerts a tumor suppressive bystander effect by stimulating exosomal secretion of Gal3, which in turn binds in a tumor-selective fashion to ¿ 1-integrin complexes due to unique N-glycanation in cancer, and induces a therapeutic effect by activating apoptosis. These studies are important because we identified a new p53-induced tumor suppressive mechanism mediated by soluble Gal3, which has therapeutic implications. Examining the role of extracellular Gal3 in glioma apoptosis and tumor growth in vivo is novel. These studies will provide proof-of-principle data for targeting cancer with Gal3 (or agonists such as peptidomimetics or small molecules). Successful outcome of this project will support the clinical translation of Gal3 for the treatment of malignant glioma and possibly other cancers, which is highly relevant to public health.

描述（由适用提供）：癌症是全球一个主要的健康问题，需要新的疗法，尤其是对于胶质母细胞瘤而言，癌症是最致命的脑肿瘤。在我们实验室中未发表的研究表明，对肿瘤抑制p53产生了新的旁观者效应。化学疗法或辐射疗法激活后，p53诱导相邻肿瘤细胞的死亡，同时诱发正常细胞。我们发现效应机制依赖于galectin-3的分泌，即诱导凋亡的一种 - 半乳糖 - 识别的讲座。我们还发现，分泌的Galectin-3在体内减少了肿瘤的形成。在此提案中，我们将通过解剖潜在机制来扩展这些初始发现，并确定GAL3是否具有临床潜力。我们将通过细胞外半乳糖素-3在肿瘤细胞中激活的凋亡信号通路的类型（AIM 1），无论是分泌的Galectin-3是否选择性地结合具有特异性细胞表面受体，具有特异性特异性特异性特异性（AIM 2），以及GAL-3是否可以用作使用InVivo Hiles Glioma模型的癌症的GAL-3递送。我们的工作假设是，p53通过刺激GAL3的外泌体分泌来发挥肿瘤抑制旁观者的作用，而GAL3的外泌体分泌又以肿瘤选择性的方式结合–1-整合蛋白复合物，这是由于癌症中独特的N-聚糖而引起的，并通过激活凋亡诱导了治疗作用。这些研究很重要，因为我们确定了由固体Gal3介导的新的P53诱导的抑制肿瘤抑制机制，该机制具有治疗意义。研究细胞外GAL3在体内肿瘤凋亡和肿瘤生长中的作用是新颖的。这些研究将提供用于用GAL3（或激动剂（例如肽仪或小分子））靶向癌症的原则数据。该项目的成功结果将支持GAL3的临床翻译，以治疗恶性神经胶质瘤和可能与公共卫生高度相关的其他癌症。