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

基本信息

批准号：
9263282
负责人：
M. CELESTE SIMON
金额：
$ 49.81万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/9263282
关键词：
Affect Allografting Attenuated Binding Cell Line Cell Maintenance Cell Proliferation Cell surface Cells Clear Cell Connective Tissue Correlative Study Diagnosis Distant Metastasis Environment Enzymes Epithelial Cells Exhibits Fatty acid glycerol esters Fructose-1,6-Bisphosphatase Gene Targeting Genes Genetic Genetic Engineering Genetic Transcription Gluconeogenesis Glutathione Glycolysis HIF1A gene Human Hypoxia Hypoxia Inducible Factor In Vitro Kidney Malignant Epithelial Cell 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 Renal Cell Carcinoma Reporting Research Proposals Resistance Role Sampling Signal Transduction Soft tissue sarcoma Solid Neoplasm Stem cells Testing Tissues Tubular formation Tumor Suppressor Proteins Undifferentiated 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-like cell targeted agent tumor tumor metabolism tumorigenesis

项目摘要

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.

项目概要/摘要肉瘤是一组异质性恶性肿瘤，起源于中胚层衍生组织，例如在美国，有近 20,000 人分别被诊断出肌肉、脂肪和结缔组织。年，大约 40% 的患者死于局部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不良的条件下茁壮成长并增殖和生长为了在这种环境中生存，肉瘤劫持了两种适应性机制：（1）激活缺氧诱导因子 1α (HIF-1α)，可增强介导肿瘤的 150 多个基因的转录代谢、血管生成和转移以及（2）利用有氧糖酵解（又名瓦伯格效应），它通过糖酵解而不是氧化磷酸化产生能量。对于肿瘤细胞亚群尤其重要，我们将其称为“肉瘤干细胞样细胞”或 SSC，在初步研究中，我们发现 SSC 具有自我更新和分化的能力。这些区域优先存在于缺氧肿瘤中，表现出 HIF-1α 水平升高，并且可能促进化疗耐药和转移。糖酵解的逆反应是糖异生，其中果糖-1, 6-二磷酸酶 (FBP) 是一种限速酶，我们最近还确定 FBP2 是一种限速酶。与正常人中胚层来源的相比，在 8 种人类肉瘤亚型中持续下调该提案的长期目标是扩大针对 HIF-1α 和 FBP2 的药物的使用。肉瘤患者可减少复发、远处转移和化疗耐药。经过检查，该提案旨在检验 HIF-1α 和 FBP2 发挥关键和相互作用的假设调节肉瘤发生、代谢、转移和化疗耐药性的相关作用。根据这一假设，本研究计划将 (1) 定义 FBP2 在肉瘤代谢中的作用， (2)确定HIF-1α在SSC转移中的作用和该提案的方法包括分析自体和异种移植物。肉瘤小鼠模型、体外肉瘤细胞系分析、代谢研究和相关研究来自肉瘤患者的肿瘤样本。