Pathway-Specific NF-kappaB Regulatory Networks in Glioma

神经胶质瘤中通路特异性 NF-kappaB 调节网络

基本信息

批准号：
8697269
负责人：
RAQUEL SITCHERAN
金额：
$ 29.5万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8697269
关键词：
Abbreviations Affect Anoikis Attenuated Biological Assay Cell Survival Cells Cellular Morphology Collagen Complement Factor B Cues Data Environment Family Genes Glioma Glossary Growth Growth Factor Inhibition Heterogeneity Human Link Malignant Neoplasms Mediator of activation protein Mesenchymal NF-kappa B Nuclear Oncogenic Pathogenesis Pathway interactions Phenotype Phosphotransferases Population Proteins Proto-Oncogene Protein c-met Reporting Research Resistance Role Signal Pathway Signal Transduction Small Interfering RNA Stem cells Testing Transforming Growth Factors Tumor Biology Xenograft procedure base cancer stem cell cancer therapy cell growth cell type design effective therapy efficacy testing epithelial to mesenchymal transition extracellular in vivo inhibitor/antagonist insight interest kinase inhibitor leukemia inhibitory factor mouse model neoplastic cell novel novel therapeutics outcome forecast pluripotency protein B protein expression public health relevance research study self-renewal small hairpin RNA stem cell population stemness trait transcription factor tumor tumor growth tumor initiation tumorigenesis tumorigenic

Abbreviations Affect Anoikis Attenuated Biological Assay Cell Survival Cells Cellular Morphology Collagen Complement Factor B Cues Data Environment Family Genes Glioma Glossary Growth Growth Factor Inhibition Heterogeneity Human Link Malignant Neoplasms Mediator of activation protein Mesenchymal NF-kappa B Nuclear Oncogenic Pathogenesis Pathway interactions Phenotype Phosphotransferases Population Proteins Proto-Oncogene Protein c-met Reporting Research Resistance Role Signal Pathway Signal Transduction Small Interfering RNA Stem cells Testing Transforming Growth Factors Tumor Biology Xenograft procedure base cancer stem cell cancer therapy cell growth cell type design effective therapy efficacy testing epithelial to mesenchymal transition extracellular in vivo inhibitor/antagonist insight interest kinase inhibitor leukemia inhibitory factor mouse model neoplastic cell novel novel therapeutics outcome forecast pluripotency protein B protein expression public health relevance research study self-renewal small hairpin RNA stem cell population stemness trait transcription factor tumor tumor growth tumor initiation tumorigenesis tumorigenic

展开

项目摘要

DESCRIPTION (provided by applicant): High-grade gliomas have one of worst prognoses among all types of human cancers and the efficacy of current therapies remains poor. We are interested in the role of the NF-?B transcription factor family as a key regulator of glioma cancer stem cells (CSCs), which are proposed to give rise to tumor cell heterogeneity and invasive growth. To-date, anti-NF-?B cancer therapy strategies have focused on targeting canonical NF-?B (RelA/IKK¿) activation without consideration of the non-canonical NF-?B pathway (RelB/IKK¿). Based on our recent findings that RelB promotes oncogenesis in mesenchymal glioma (Lee et al. PLOS One, 2013), we argue that there is a critical need to understand how specific NF-?B signaling pathways contribute to tumor initiation/ progression. Specifically, we propose that canonical and non-canonical NF-?B signaling may be particularly important in different glioma subtypes, as well as distinct cancer stem cell populations. Recent studies suggest an intimate relationship between transforming growth factor ¿ (TGF¿)-induced epithelial-to-mesenchymal transition (EMT) and CSCs survival and invasion. However, the role of EMT and CSC survival in glioma is unclear. Based on preliminary data, we propose to 1) determine which NF-?B proteins and upstream signaling pathways are activated in different glioma subtypes and CSCs; 2) evaluate the role of specific NF-?B proteins in promoting self-renewal and pluripotency in distinct CSC populations; and 3) test the effects of inhibiting IKK/NF-?B on glioma CSC survival, invasion and tumor growth in vivo. A better understanding of the mechanisms regulating glioma stem-cell self-renewal and differentiation will not only reveal new insights into glioma tumor biology, but will also facilitate identifying novel approache to target the key cells responsible for tumor heterogeneity and treatment resistance.

描述（由适用提供）：高级神经胶质瘤在所有类型的人类癌症中都具有最糟糕的预后，并且当前疗法的效率仍然很差。我们对NF-？B转录因子家族的作用感兴趣干细胞（CSC），提议引起肿瘤细胞的异质性和侵入性生长。迄今为止，抗NF-？B癌症治疗策略的重点是靶向规范的NF-？B（Rela/Ikk？）激活，而无需考虑非典型的NF-？B途径（RELB/IKK®）。基于我们最近的发现，RERB促进了间充质神经胶质瘤中的肿瘤发生（Lee等人PLOS One，2013），我们认为有迫切需要了解特定的NF-be-b信号传导途径如何有助于肿瘤起始/进展。具体而言，我们建议在不同的神经胶质瘤亚型以及独特的癌症干细胞种群中，规范和非规范的NF-信号传导可能尤其重要。最近的研究表明，转化生长因子（TGF¿）诱导的上皮 - 间质转变（EMT）与CSC的生存和入侵之间存在密切的关系。然而，EMT和CSC在神经胶质瘤中存活的作用尚不清楚。基于初步数据，我们建议1）确定在不同的神经胶质瘤亚型和CSC中激活了哪些NF-蛋白和上游信号通路； 2）评估特定NF-蛋白在促进不同CSC种群中自我更新和多能性中的作用； 3）测试抑制IKK/NF-？B对胶质瘤CSC存活，侵袭和体内肿瘤生长的影响。更好地理解机制调节神经胶质瘤干细胞自我更新和分化不仅会揭示对神经胶质瘤肿瘤生物学的新见解，而且还将促进识别新的方法，以瞄准负责肿瘤异质性和耐药性的钥匙细胞。