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：
9033869
负责人：
ERWIN G VAN MEIR
金额：
$ 32.37万
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/9033869
关键词：
Adult Agonist Animal Lectins Animal Model Animals Apoptosis Apoptotic BH3 Domain Binding Binding Proteins Biodistribution Brain Neoplasms Bystander Effect C-terminal CASP9 gene 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 TP53 gene Testing Therapeutic Therapeutic Agents Therapeutic Effect Tissues Toxic effect Translations Work anti-cancer therapeutic base cancer cell cancer therapy cell growth cell killing chemotherapy differential expression experience extracellular glycosylation in vivo inhibitor/antagonist innovation insight killings neoplastic cell novel novel therapeutics peptidomimetics prevent 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 Unpublished studies in our lab have revealed a new bystander effect for tumor suppressor p53.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（由申请人提供）：癌症是世界范围内的一个主要健康问题，迫切需要新的治疗方法，特别是对于胶质母细胞瘤（最致命的脑肿瘤），我们实验室未发表的研究揭示了化疗激活肿瘤抑制因子 p53 的新旁观者效应。 - 或放射疗法 p53 诱导邻近肿瘤细胞死亡，同时保留正常细胞。我们发现效应机制依赖于半乳糖凝集素 3（一种 ¿）的分泌。 -半乳糖识别凝集素，可诱导细胞凋亡。在本提案中，我们将通过剖析潜在机制来扩展这些初步发现，并确定 Gal3 是否具有临床潜力。细胞外半乳糖凝集素 3 在肿瘤细胞中激活的凋亡信号通路类型（目标 1），分泌的半乳糖凝集素 3 是否选择性结合特定的细胞表面受体，具有肿瘤特异性特征（目标 2），以及 Gal-3 递送是否可以作为使用体内小鼠神经胶质瘤模型的癌症的可行治疗方法（目标 3）。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效应。，反过来又以肿瘤选择性的方式结合到 ¿ 1-整合素复合物归因于癌症中独特的 N-聚糖化，并通过激活细胞凋亡来诱导治疗效果。这些研究很重要，因为我们发现了一种由可溶性 Gal3 介导的新的 p53 诱导的肿瘤抑制机制，该机制具有治疗意义。细胞外 Gal3 在神经胶质瘤细胞凋亡和体内肿瘤生长中的作用是新颖的，这些研究将为 Gal3（或激动剂等）靶向癌症提供原理验证数据。该项目的成功成果将支持 Gal3 用于治疗恶性胶质瘤和可能的其他癌症的临床转化，这与公共健康高度相关。