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

项目总结/摘要 肉瘤是一组异质性的恶性肿瘤，来源于中胚层来源的组织，如 肌肉脂肪和结缔组织在美国，每种疾病的确诊人数接近2万人。 大约40%的患者死于局部复发或远处转移。 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， 转移为了在这样的环境中生存，肉瘤劫持了两种适应机制：（1）激活 缺氧诱导因子1α（hypoxia inducible factor 1α，HIF-1α）可促进150多个肿瘤相关基因的转录 代谢、血管生成和转移;和（2）利用有氧糖酵解（a.k.a.瓦尔堡效应）， 其通过糖酵解而不是氧化磷酸化产生能量。HIF-1α似乎是 对于我们称为“肉瘤干细胞样细胞”或SSC的肿瘤细胞亚群特别关键， 具有自我更新和分化的能力。在初步研究中，我们发现SSC 优先存在于肿瘤的缺氧区域，表现出HIF-1α水平升高，并可能促进肿瘤的生长。 化疗耐药和转移。糖酵解的逆反应是糖异生， 果糖-1，6-二磷酸酶（FBP）起限速酶的作用。我们最近还确定FBP 2是 与正常人中胚层来源的肿瘤细胞相比， 组织中该提案的长期目标是扩大靶向HIF-1α和FBP 2的药物在肿瘤中的应用。 肉瘤患者，以减少复发，远处转移和化疗耐药性。 因此，本研究旨在验证HIF-1α和FBP 2在细胞凋亡中起关键作用的假设。 在调节肉瘤发生、代谢、转移和化疗抗性中的相关作用。测试 这个假设，这个研究计划将（1）定义FBP 2在肉瘤代谢中的作用， （2）确定HIF-1α在SSC转移中的作用， 化疗耐药性该建议的方法包括分析自体和异种移植 肉瘤小鼠模型、体外肉瘤细胞系分析、代谢研究和相关研究 肉瘤患者的肿瘤样本。

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.