HYPOXIC STRESS MECHANISMS IN RADIATION AND CHEMOTHERAPY

放射治疗和化疗中的缺氧应激机制

基本信息

批准号：
7324833
负责人：
BRIAN J MURPHY
金额：
$ 33.66万
依托单位：
SRI INTERNATIONAL
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-12 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7324833
关键词：
Address Attenuated Binding Biopsy Breast Breast Cancer Cell Breast Carcinoma Cancer cell line Carcinoma Cell Line Cells Cervix Neoplasms Cisplatin Cytoskeleton Deposition Development Disease Dorsal Embryo Embryonic Development Epithelial Etoposide Experimental Neoplasms Extracellular Signal Regulated Kinases Factor V Failure Fibroblasts Fibrosis Gelatinase A Genes Genetic Genetic Transcription Glucosephosphate Dehydrogenase Growth Head and neck structure Human Hypoxia Hypoxia Inducible Factor Immune response Knock-out Knockout Mice Laboratories Lead Lung MCF7 cell MEKs Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Matrix Metalloproteinases Mediating Membrane Metallothionein Metals Mitogen-Activated Protein Kinases Modality Modeling Molecular Mus Nude Mice Numbers Oncogenic Oxidants Oxidation-Reduction Pathway interactions Physiological Placental Growth Factor Play Process Property Protein Family Protein Overexpression Proteins Radiation Radio Regulation Regulatory Pathway Relative (related person)Research Personnel Resistance Role Signal Pathway Signal Transduction Skin Solid Neoplasm Stress Surgical Flaps Therapeutic Intervention Thinking Time Tissues Transcriptional Regulation Transforming Growth Factors Transgenic Mice Transglutaminases Translations Work Xenograft Model Xenograft procedure angiogenesis base cell motility chemotherapy cisplatin/doxorubicin protocol design fibrosarcoma host neoplasm interaction human FRAP1 protein hypoxia inducible factor 1 in vivo Model malignant breast neoplasm mortality neoplastic neoplastic cell novel prognostic programs protective effect radiation resistance response therapeutic angiogenesis therapy resistant tirapazamine transcription factor transglutaminase 2 tumor tumor growth tumor initiation tumor progression tumorigenesis tumorigenic zinc-binding protein

项目摘要

The metal transcription factor-1 (MTF-1) is a metal and redox-sensitive protein that is essential for embryonic development and involved in the transcriptional regulation of a growing number of tumor-related proteins including metallothionein, placenta growth factor, zinc transporter-1, glucose-6-phosphate, dehydrogenase, and matrix metalloproteinases. This laboratory has found MTF-1 to be highly expressed in human carcinomas and to be positively associated with the metastatic potential of human breast cancer cell lines. The genetic loss of MTF-1 results in suppression of experimental tumor growth and angiogenesis through enhanced deposition of extra-cellular matrix, caused in part by increased expression and activation of the transforming growth factor-pi and tissue transglutaminase, and attenuated expression of some matrix metalloproteinases. This group has also found MTF-1 to be involved in chemo- and radio-resistance, to contribute to the accumulation of the hypoxia-inducible factor-1 a (HIF-la) in response to hypoxia, and to be implicated in hypoxia-inducible signaling through two central mitogen activated protein kinase pathways. The first set of studies (Specific Aim 1)will address the putative role of MTF-1 in conferring chemo- and radio-resistance and translational relevance using human xenografts. It will also assess downstream contributions from HIF-la, and other specific signaling pathways. Aim 2 will define the underlying molecular mechanisms involved hi the regulation of HEF-la accumulation by MTF-1. An understanding of this regulatory pathway is important since HIF-la is believed to play a key role in tumorigenesis, angiogenesis and therapy resistance. Aim 3 will address the interaction between tumor and host cells in the initiation and progression of tumor growth as a function of MTF-1 expression utilizing MTF-1 conditional knockout mice and conditional knockout cell lines. The relative roles of MTF-1 and HIF-la in angiogenesis and initiation of tumor development, using the novel dorsal skin flap window chamber model, will also be addressed. An understanding of these MTF-1-dependent properties should aid in the development of novel prognostic and new modalities for neoplastic diseases.

金属转录因子-1 (MTF-1) 是一种金属和氧化还原敏感蛋白，对于胚胎发育并参与越来越多的肿瘤相关的转录调控蛋白质，包括金属硫蛋白、胎盘生长因子、锌转运蛋白-1、葡萄糖-6-磷酸、脱氢酶和基质金属蛋白酶。本实验室发现MTF-1在人类癌症并与人类乳腺癌细胞的转移潜力呈正相关线。 MTF-1 基因缺失导致实验性肿瘤生长和血管生成受到抑制通过增强细胞外基质的沉积，部分是由于细胞外基质的表达和激活增加所致转化生长因子-pi 和组织转谷氨酰胺酶，以及某些基质的减弱表达金属蛋白酶。该小组还发现 MTF-1 参与化学和放射抗性，以有助于缺氧诱导因子 1a (HIF-la) 的积累以应对缺氧，并且通过两个中央丝裂原激活蛋白激酶途径参与缺氧诱导信号传导。第一组研究（具体目标 1）将探讨 MTF-1 在赋予化疗和使用人类异种移植物的放射抗性和翻译相关性。它还将评估下游 HIF-1α 和其他特定信号通路的贡献。目标 2 将定义底层分子机制涉及MTF-1对HEF-1α积累的调节。的理解该调节途径很重要，因为 HIF-1α 被认为在肿瘤发生中发挥关键作用，血管生成和治疗抵抗。目标 3 将解决肿瘤和宿主细胞之间的相互作用利用 MTF-1 条件作为 MTF-1 表达函数的肿瘤生长的启动和进展基因敲除小鼠和条件性基因敲除细胞系。 MTF-1和HIF-1α在血管生成中的相对作用使用新型背侧皮瓣窗室模型也将启动肿瘤的发展已解决。了解这些 MTF-1 依赖性特性应该有助于开发新的肿瘤疾病的预后和新方法。