HIF-1alpha and FBP2 in sarcoma metabolism, progression, and metastasis

HIF-1α 和 FBP2 在肉瘤代谢、进展和转移中的作用

• 批准号: 10059906
• 负责人: M. CELESTE SIMON
• 金额: $ 7.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059906
• 关键词: Affect; Allografting; Attenuated; Binding; Cell Line; Cell Maintenance; Cell Proliferation; Cell surface; Cells; Clear cell renal cell carcinoma; Connective Tissue; Correlative Study; Diagnosis; Distant Metastasis; Environment; Enzymes; Epithelial Cells; Exhibits; Fatty acid glycerol esters; Fructose-1,6-Bisphosphatase; Genes; Genetic; Genetic Engineering; Genetic Transcription; Gluconeogenesis; Glutathione; Glycolysis; HIF1A gene; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Kidney; Malignant Epithelial Cell; Malignant Fibrous Histiocytoma; Malignant Neoplasms; Mediating; Mesoderm; Metabolism; Metastatic Neoplasm to the Lung; Methods; Modeling; Mus; Muscle; Neoplasm Metastasis; Nuclear; Nutrient; Oxidative Phosphorylation; Patients; Pentosephosphate Pathway; Persons; Phenotype; Play; Proliferating; Property; Reaction; Recurrence; Reporting; Research Proposals; Resistance; Role; Sampling; Signal Transduction; Soft tissue sarcoma; Solid Neoplasm; Testing; Tissues; Tubular formation; Tumor Suppressor Proteins; United States; VEGFA gene; Warburg Effect; Xenograft procedure; aerobic glycolysis; angiogenesis; beta catenin; chemotherapy; design; macromolecule; metabolic abnormality assessment; migration; mouse model; neoplastic cell; novel; overexpression; prevent; progenitor; restoration; sarcoma; self-renewal; stem cells; stem-like cell; targeted agent; tumor; tumor metabolism; tumorigenesis

Project Summary/Abstract Sarcomas are a heterogeneous group of malignancies arising from mesoderm-derived tissues such as muscle, fat, and connective tissue. They are diagnosed in nearly 20,000 persons in the United States each year, and approximately 40% of patients die of either loco-regional recurrence or distant metastasis. Sarcomas and other solid tumors typically thrive in hypoxic and nutrient-poor conditions to proliferate and metastasize. To survive in such environments, sarcomas hijack two adaptive mechanisms: (1) activation of hypoxia inducible factor 1α (HIF-1α), which enhances the transcription of over 150 genes mediating tumor metabolism, angiogenesis, and metastasis and (2) utilization of aerobic glycolysis (a.k.a. the Warburg effect), which creates energy by means of glycolysis rather than oxidative phosphorylation. HIF-1α appears to be particularly critical for a subset of tumor cells which we will refer to as “sarcoma stem-like cells” or SSCs, characterized by their ability to self renew and differentiate. In preliminary studies, we have found that SSCs reside preferentially in hypoxic regions of tumors, exhibit elevated levels of HIF-1α, and are likely to promote chemotherapy resistance and metastasis. The reverse reaction of glycolysis is gluconeogenesis, where fructose-1, 6-bisphosphatase (FBP) acts as a rate-limiting enzyme. We also recently determined that FBP2 is consistently downregulated in 8 human sarcoma subtypes compared to normal human mesoderm-derived tissues. The long-term objective of this proposal is to expand the use of agents targeting HIF-1α and FBP2 in patients with sarcomas to reduce recurrence, distant metastasis, and chemotherapy resistance. Consequently, this proposal is designed to test the hypothesis that HIF-1α and FBP2 play critical and inter- related roles in regulating sarcomagenesis, metabolism, metastasis, and chemotherapy resistance. To test this hypothesis, this research proposal will (1) define the role of FBP2 in sarcoma metabolism, progression, and metastasis, and (2) determine the role of HIF-1α in SSC metastasis and chemotherapy resistance. The methods of this proposal include analysis of autochthonous and xenograft mouse models of sarcomas, analysis of sarcoma cell lines in vitro, metabolic studies, and correlative studies of tumor samples from sarcoma patients.

项目摘要/摘要 肉瘤是由中胚层衍生的组织（例如 肌肉，脂肪和连接的组织。他们在美国被诊断出近20,000人 一年，大约40％的患者死于现场区域复发或远处转移。 肉瘤和其他实体瘤通常在缺氧和营养贫困的条件下繁殖，以增殖和 转移。为了在这种环境中生存，肉瘤劫持了两种自适应机制：（1）激活 低氧诱导因子1α（HIF-1α），增强了介导肿瘤的150多个基因的转录 代谢，血管生成和转移以及（2）有氧糖酵解的利用（又称Warburg效应）， HIF-1α似乎是 对于肿瘤细胞的子集特别重要，我们将其称为“肉瘤样细胞”或SSC， 其特征是他们自我更新和区分的能力。在初步研究中，我们发现SSCS 最好驻留在肿瘤的低氧区域，表现出HIF-1α水平升高，可能会促进 化学疗法抗性和转移。糖酵解的反反应是糖化作用，其中 果糖1，6-二磷酸酶（FBP）充当限速酶。我们最近还确定FBP2是 与正常的中胚层相比，在8种人类肉瘤亚型中始终下调 组织。该提案的长期目的是扩大针对HIF-1α和FBP2的代理的使用 患有肉瘤的患者可减少复发，远处转移和抗化疗性。 因此，该提案旨在检验HIF-1α和FBP2的假设 相关的作用在确定肌瘤发生，代谢，转移和化学疗法耐药性方面。测试 这个假设，该研究建议将（1）定义FBP2在肉瘤代谢中的作用， 进展和转移，（2）确定HIF-1α在SSC转移和 化学疗法抗性。该提案的方法包括对自动和异种移植的分析 肉瘤的小鼠模型，体外肉瘤细胞系的分析，代谢研究和相关研究 肉瘤患者的肿瘤样品。