Hypoxia and HIF in Sarcomagenesis

肉瘤发生中的缺氧和 HIF

• 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
• 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

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）是肉瘤中最具侵袭性和最常诊断的亚型，具有高度转移性。瘤内缺氧被认为可以促进肉瘤（包括 MFH）向远处转移。然而，这一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 肉瘤的标志物。 FOXM1 表达的调节在肉瘤中可能特别重要，因为 FOXM1 与许多其他人类癌症的肿瘤形成和转移有关。 HIF 和 FOXM1 都是 Ras 通路的潜在下游效应子，Ras 突变存在于高达 50% 的 MFH 肿瘤中。该提议的中心假设是缺氧肉瘤中 HIF 活性增加，促进 FOXM1 的表达和转移。基于这个假设，我将追求三个具体目标。具体目标1：确定缺氧和HIF对体外肉瘤细胞系增殖、凋亡和衰老的影响和潜在分子机制。具体目标 2：确定肉瘤细胞系中缺氧和 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：使用肉瘤和人类异种移植肿瘤的诱导型小鼠模型检查 HIF 和 FOXM1 在体内的作用。为了完成这些研究，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。本研究计划的目的是阐明缺氧和 HIF 依赖性肉瘤形成和进展的潜在机制。这些研究的长期目标将是确定新的治疗靶点，这将有助于肉瘤的新治疗，并提供有关一般肿瘤形成和肺部转移的重要线索。