Effect of HIF-1alpha on tumor response to antiangiogenesis

HIF-1α 对肿瘤抗血管生成反应的影响

• 批准号: 7076181
• 负责人: LONG H DANG
• 金额: $ 15.85万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7076181
• 关键词: angiogenesis inhibitors; apoptosis; athymic mouse; cell line; cell migration; drug resistance; glucose metabolism; glucose transport; hypoxia; hypoxia inducible factor 1; metastasis; molecular oncology; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; neoplastic growth; protein structure function; xenotransplantation

DESCRIPTION (provided by applicant): Cancer development relies on the dynamic balance between cancer epithelial cells and the tumor vasculature. Thus, antiangiogenic therapy is a rational and effective approach against tumor growth and progression. Vascular endothelial growth factor A (VEGFA or VEGF) is a well-proven dominant growth factor in tumor angiogenesis, which has been further substantiated by the clinical promise of targeting VEGF in the treatment of human cancers. The HIF-1 transcription factor complex (HIF-1a/HIF-1B) plays an essential role in the response of cancer cells to hypoxia. Extensive evidence shows that HIF-1 induces the expression of genes important in hypoxia response such as anti-apoptosis, glycolysis, angiogenesis, cell migration, and metastasis. However, it remains unclear whether HIF-1a solely mediates tumor survival under hypoxia; or whether redundant pathways contribute to mechanisms of survival. For example, the HIF-2 complex (HIF-2a/HIF-1B) may also regulate genes important in hypoxia response. A growing concern with effective antiangiogenic therapy is tumor reactive resistance: The resulting increase in intratumoral hypoxia may drive the selection of cells that are less dependent on the vasculature, cells which in turn may be more malignant. While reactive resistance is thought to be driven by hypoxia, it remains to be determined whether reactive resistance is mediated by HIFs (HIF-1a and HIF-2B). The primary aim of this proposal is to determine the direct role of HIF-1a in mediating tumor response to antiangiogenic therapy. The secondary aim is to distinguish the roles of HIF-1a and HIF-2B in tumor response to hypoxic stress. To directly investigate these aims, a pre-clinical model system, using human cancer cell knockout technology, was developed. The insights gained from these studies should contribute to our understanding of cancer biology and the rational combination of antiangiogenic therapies.

描述（由申请人提供）：癌症发展取决于癌症上皮细胞与肿瘤脉管系统之间的动态平衡。因此，抗血管生成疗法是针对肿瘤生长和进展的一种理性有效的方法。血管内皮生长因子A（VEGFA或VEGF）是肿瘤血管生成中良好的主要生长因子，这已通过针对人类癌症治疗VEGF的临床承诺进一步证实。 HIF-1转录因子复合物（HIF-1A/HIF-1B）在癌细胞对缺氧的反应中起着至关重要的作用。大量证据表明，HIF-1诱导基因在缺氧反应中重要的基因表达，例如抗凋亡，糖酵解，血管生成，细胞迁移和转移。但是，尚不清楚HIF-1A是否仅在缺氧下介导肿瘤存活。还是冗余途径是否有助于生存机制。例如，HIF-2复合物（HIF-2A/HIF-1B）也可能调节在缺氧反应中重要的基因。对有效的抗血管生成疗法的越来越多的关注是肿瘤反应性抗性：导致肿瘤内缺氧的增加可能会驱动较少依赖脉管系统的细胞的选择，而细胞又可能更恶性。尽管被认为是由缺氧驱动的，但仍有待确定反应性抗性是否由HIF（HIF-1A和HIF-2B）介导。该建议的主要目的是确定HIF-1A在介导肿瘤对抗血管生成疗法反应中的直接作用。次要目的是区分HIF-1A和HIF-2B在肿瘤对低氧应激反应中的作用。为了直接研究这些目标，开发了使用人类癌细胞敲除技术的临床前模型系统。从这些研究中获得的见解应有助于我们对癌症生物学的理解和抗血管生成疗法的合理组合。