Hypoxia and HIF in Sarcomagenesis

肉瘤发生中的缺氧和 HIF

基本信息

批准号：
8326371
负责人：
Tzipora Sarah Karin Eisinger
金额：
$ 1.87万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8326371
关键词：
Adenoviruses Adipose tissue Adult Age Animal Model Animals Apoptosis Apoptosis Regulator Biochemistry Boxing Breast CDKN2A gene Cartilage Cell Line Cell Proliferation Cell Survival Cell physiology Cells Cellular biology Characteristics Clear Cell Clinical Colon Colonic Neoplasms Connective Tissue Development Diagnosis Disease Distant Extracellular Matrix Gelatinase A Gelatinase B Genes Genetic Goals Hepatic Human Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Immunodeficient Mouse Immunohistochemistry In Vitro Integrins Intramuscular Injections Kidney Lung Lung Neoplasms Malignant - descriptor Malignant Fibrous Histiocytoma Malignant Neoplasms Mammary Neoplasms Mediating Mesenchymal Metastatic Malignant Fibrous Histiocytoma Metastatic Neoplasm to the Lung Methods Microarray Analysis Molecular Mus Muscle Muscle Cells Mutate Mutation Neoplasm Metastasis Outcome Oxidative Stress Oxygen Pathway interactions Patients Play Process Radiosurgery Regulation Research Proposals Role Signal Transduction Site Solid Neoplasm Staging Survival Rate Tissues Tumor-Derived Undifferentiated Vascularization Xenograft Model Xenograft procedure base biological adaptation to stress c-myc Genes catalase cell motility chemotherapy hypoxia inducible factor 1 in vivo migration mouse model new therapeutic target overexpression p19ARF programs recombinase response sarcoma senescence soft tissue therapeutic target transcription factor tumor tumor xenograft tumorigenesis

Adenoviruses Adipose tissue Adult Age Animal Model Animals Apoptosis Apoptosis Regulator Biochemistry Boxing Breast CDKN2A gene Cartilage Cell Line Cell Proliferation Cell Survival Cell physiology Cells Cellular biology Characteristics Clear Cell Clinical Colon Colonic Neoplasms Connective Tissue Development Diagnosis Disease Distant Extracellular Matrix Gelatinase A Gelatinase B Genes Genetic Goals Hepatic Human Hypoxia Hypoxia Inducible Factor Hypoxia-Inducible Factor Pathway Immunodeficient Mouse Immunohistochemistry In Vitro Integrins Intramuscular Injections Kidney Lung Lung Neoplasms Malignant - descriptor Malignant Fibrous Histiocytoma Malignant Neoplasms Mammary Neoplasms Mediating Mesenchymal Metastatic Malignant Fibrous Histiocytoma Metastatic Neoplasm to the Lung Methods Microarray Analysis Molecular Mus Muscle Muscle Cells Mutate Mutation Neoplasm Metastasis Outcome Oxidative Stress Oxygen Pathway interactions Patients Play Process Radiosurgery Regulation Research Proposals Role Signal Transduction Site Solid Neoplasm Staging Survival Rate Tissues Tumor-Derived Undifferentiated Vascularization Xenograft Model Xenograft procedure base biological adaptation to stress c-myc Genes catalase cell motility chemotherapy hypoxia inducible factor 1 in vivo migration mouse model new therapeutic target overexpression p19ARF programs recombinase response sarcoma senescence soft tissue therapeutic target transcription factor tumor tumor xenograft tumorigenesis

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项目摘要

DESCRIPTION (provided by applicant): Soft tissue sarcomas are solid tumors derived from mesenchymal cells of muscle, connective tissue, and cartilage. Malignant fibrous histiocytoma (MFH), the most aggressive and most commonly diagnosed subtype of sarcoma is highly metastatic. Intratumoral hypoxia has been proposed to facilitate metastasis of sarcomas, including MFH, to distant sites. However, the molecular basis of this process is unknown. Recently, hypoxia inducible factor (HIF)11 and several of its transcriptional targets, including the transcription factor FOXM1, have been identified as markers of metastatic MFH sarcoma by microarray analysis. Regulation of FOXM1 expression may be particularly important in sarcomas, as FOXM1 has been associated with tumor formation and metastasis in numerous other human cancers. Both HIF and FOXM1 are potential downstream effectors of the Ras pathway and Ras mutations are found in up to 50% of MFH tumors. The central hypothesis of this proposal is that HIF activity is increased in hypoxic sarcomas, promoting expression of FOXM1 and metastasis. Based on this hypothesis I will pursue three specific aims. Specific Aim 1: To determine the effects and underlying molecular mechanisms of hypoxia and HIF on proliferation, apoptosis, and senescence of sarcoma cell lines in vitro. Specific Aim 2: To define the effects and molecular basis of hypoxia and HIF- mediated migration/invasion and oxidative stress responses in sarcoma cell lines. Specific Aim 3: To examine the role of HIFs and FOXM1 in vivo using an inducible mouse model of sarcoma and human xenograft tumors. To complete these studies I will combine in vitro and in vivo methods of cell biology, biochemistry, immunohistochemistry, genetics, and animal modeling. The objective of this research proposal is to elucidate the underlying mechanisms of hypoxia and HIF-dependent sarcoma formation and progression. The long-term goal of these studies will be to identify novel therapeutic targets, which will facilitate new treatments for sarcoma and provide important clues about general tumor formation and metastasis to the lung.

描述（由申请人提供）：软组织肉瘤是源自肌肉，结缔组织和软骨的间充质细胞的实体瘤。恶性纤维组织细胞瘤（MFH），最具侵略性，最常见的肉瘤亚型是高度转移性的。已经提出了肿瘤内缺氧，以促进包括MFH在内的肉瘤转移到远处的位置。但是，该过程的分子基础尚不清楚。最近，通过微阵列分析，缺氧诱导因子（HIF）11及其几个转录靶标（包括转录因子FOXM1）已被鉴定为转移性MFH肉瘤的标记。 FOXM1表达的调节在肉瘤中可能尤其重要，因为FOXM1与许多其他人类癌症中的肿瘤形成和转移有关。 HIF和FOXM1都是RAS途径的潜在下游效应子，在多达50％的MFH肿瘤中发现RAS突变。该提议的中心假设是缺氧性肉瘤中的HIF活性增加，从而促进了FOXM1和转移的表达。基于这个假设，我将追求三个具体目标。具体目的1：确定缺氧和HIF的影响和潜在的分子机制对体外肉瘤细胞系的增殖，凋亡和衰老。具体目的2：定义缺氧和HIF介导的迁移/侵袭和氧化应激反应的影响和分子基础。具体目标3：使用肉瘤和人异种移植肿瘤的诱导小鼠模型检查HIF和FOXM1在体内的作用。要完成这些研究，我将结合细胞生物学，生物化学，免疫组织化学，遗传学和动物建模的体外和体内方法。该研究建议的目的是阐明缺氧和HIF依赖性肉瘤的形成和进展的潜在机制。这些研究的长期目标是确定新型的治疗靶标，这将促进肉瘤的新治疗方法，并为肺部的一般肿瘤形成和转移提供重要线索。