Mechanisms of the hypoxic response underlying tumor progression

肿瘤进展的缺氧反应机制

基本信息

批准号：
7583435
负责人：
L. Eric Huang
金额：
$ 31.23万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7583435
关键词：
Address Allografting Anchorage-Independent Growth Biological Cancer Biology Cell Proliferation Cells Complex Coupled Cultured Cells Cultured Tumor Cells Cytogenetics DNA Damage DNA Repair DNA Repair Gene DNA Repair Pathway Development Drug Delivery Systems Epithelial Gene Activation Gene Expression Gene Expression Profiling Gene Targeting Genetic Genetic Induction Genome Genomics Germ-Line Mutation Goals Growth Hereditary Disease Hereditary Malignant Neoplasm Human Hypoxia Hypoxia Inducible Factor Immunohistochemistry In Vitro Lead Link Malignant - descriptor Malignant Neoplasms Mesenchymal Molecular Molecular Biology Molecular Biology Techniques Mutation Nature Neoplasm Metastasis Normal Cell Oncogene Activation Pathway interactions Pharmaceutical Preparations Phosphorylation Plant Roots Play Protein Isoforms Public Health Radiation therapy Reporting Resistance Role Signal Pathway Spectral Karyotyping Testing Threonine Time Tumor-Suppressor Gene Inactivation Tumorigenicity Xenograft Model Xenograft procedure angiogenesis anticancer research base c-myc Genes cancer cell cell behavior cell killing chemotherapy comparative genomic hybridization fight against functional disability in vivo insight mouse model neoplastic cell novel novel strategies novel therapeutics protein protein interaction response trait transcription factor tumor tumor growth tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Our long-term objective of this proposal is to gain an understanding at the molecular level of how the tumor microenvironment determines tumor growth and progression. Decades of cancer research has come to a conclusion that cancer is essentially a genetic disease acquiring dynamic changes in the genome. The development of cancer in humans requires a complex succession of genetic alterations over time, conferring selective growth advantage on cells undergoing progressive transformation. These genetic changes result in activation of oncogenes and inactivation of tumor-suppressor genes for tumor development. Various DNA repair mechanisms safeguard the genomic integrity in normal cells by correcting mutations arising from myriad types of damage. Germline mutations of DNA repair genes have been linked to diverse types of hereditary cancers. However, no such mutations are generally found to be responsible for the development of sporadic cancers. Apart from tumor itself, the tumor microenvironment, hypoxia in particular, has been associated with increased genetic instability in cancers, presumably attributable to tumor progression and resistance to chemotherapy and radiotherapy, even though the underlying mechanisms remain obscure. We have recently shown that the hypoxia-inducible factor 1a (HIF-1a), a central transcription factor of the hypoxic response, induces genetic instability by inhibiting DNA repair gene expression via a novel HIF-1a-c-Myc pathway, suggesting the involvement of functional impairment of DNA repair in tumor development and progression. Despite the heavy implication in tumor growth and angiogenesis, HIF-2a, an isoform of HIF-1a, fails to inhibit DNA repair because of threonine phosphorylation. In this proposal, we study the role of HIF-1a and HIF-2a in tumor development and progression. Specific Aim 1 and Specific Aim 2 test the hypothesis that the induction of genetic instability through activation of HIF-1a-Myc pathway confers malignant traits such as invasion on cultured tumor cells in vitro and tumorigenicity, local invasion, and metastasis in tumor xenograft models. Specific Aim 3 investigates the requirement of phosphorylation for HIF-2a activities and in turn tumor growth in both cell culture and mouse models We believe that this proposal addresses the fundamental mechanisms underlying the dynamic nature of tumor growth and progression and will build a molecular basis for the development of novel therapeutics. PUBLIC HEALTH RELEVANCE Cancer is, in essence, a genetic disease acquiring dynamic changes in the genome. This proposal tackles the obscure mechanisms underlying genetic instability of cancer cells, an insurmountable problem in the fight against cancer. We anticipate this study will help define the molecular basis for the development of novel therapeutics.

描述（由申请人提供）：我们的长期目标是在分子水平上了解肿瘤微环境如何决定肿瘤的生长和进展。几十年来的癌症研究得出的结论是，癌症本质上是一种遗传疾病，从而获得基因组动态变化。人类癌症的发展需要随着时间的推移进行复杂的遗传改变，从而在经历进行性转化的细胞上提供选择性的生长优势。这些遗传变化导致肿瘤基因的激活和肿瘤抑制基因的灭活以进行肿瘤发育。各种DNA修复机制通过纠正由无数类型的损伤引起的突变来保护正常细胞中的基因组完整性。 DNA修复基因的生殖线突变与多种类型的遗传癌有关。但是，通常没有发现这种突变是零星癌的发展。除肿瘤本身外，尤其是肿瘤微环境，尤其是缺氧，与癌症的遗传不稳定性增加有关，这可能归因于肿瘤的进展和耐药性，即使基本机制仍然晦涩难懂。我们最近表明，缺氧诱导因子1a（HIF-1A）是低氧反应的中心转录因子，它通过通过新型的HIF-1A-C-MYC途径抑制DNA修复基因表达来诱导遗传不稳定，这表明DNA修复功能障碍在肿瘤发育和进展中的功能障碍涉及功能障碍。尽管对肿瘤生长和血管生成有很大的影响，但HIF-2A（HIF-1A的同工型）由于苏氨酸磷酸化而无法抑制DNA修复。在此提案中，我们研究了HIF-1A和HIF-2A在肿瘤发育和进展中的作用。特定的目标1和特定目标2检验了以下假说：遗传不稳定性通过HIF-1A-MYC途径激活遗传不稳定性赋予恶性特征，例如在体外和肿瘤性肿瘤细胞中侵袭培养的肿瘤细胞，局部入侵，局部侵袭，以及肿瘤内诺治疗模型中的转移。具体目的3研究了细胞培养和小鼠模型中磷酸化对HIF-2A活性的需求以及肿瘤的生长，我们认为，该建议探讨了肿瘤生长和进展动态性质的基本机制，并将为新治疗剂的发展建立分子基础。从本质上讲，公共卫生相关性癌症是一种遗传疾病，可获得基因组动态变化。该提议解决了癌细胞遗传不稳定的晦涩机制，这是对抗癌症的一个无法克服的问题。我们预计这项研究将有助于定义新型治疗剂发展的分子基础。