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

项目摘要/摘要 肉瘤是起源于中胚层组织的一组不同种类的恶性肿瘤，例如 肌肉、脂肪和结缔组织。在美国，每个人都有近2万人被诊断出患有这种疾病 每年，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低氧和营养不良的条件下生长旺盛，能够增殖和 转移瘤。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(HIF-1α)可增强150多个肿瘤相关基因的转录 代谢、血管生成和转移；(2)有氧糖酵解的利用(又名。华宝效应)， 它通过糖酵解而不是氧化磷酸化来产生能量。HIF-1α似乎是 对肿瘤细胞的一个子集尤其关键，我们将其称为“肉瘤干细胞”或SSCs， 以自我更新和分化能力为特征的。在初步研究中，我们发现SSCs 优先位于肿瘤的缺氧区，表现出高水平的HIF-1α，并可能促进 化疗耐药和转移。糖酵解的反向反应是糖异生，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 与正常人中胚层来源的肉瘤相比，8种人肉瘤亚型的持续下调 纸巾。这项建议的长期目标是扩大针对HIF-1α和FBP2的药物在 肉瘤患者可减少复发、远处转移和化疗耐药性。 因此，这一建议旨在检验这一假设，即缺氧诱导因子-1α和Fbp2在 在调节肉瘤发生、代谢、转移和化疗耐药中的相关作用。为了测试 这一假说，这项研究建议将(1)确定FBP2在肉瘤代谢中的作用， 以及(2)确定HIF-1α在SSc转移和转移中的作用。 化疗耐药。这项建议的方法包括分析自体移植和异种移植。 小鼠肉瘤模型、肉瘤细胞株体外分析、代谢研究及相关研究 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.