Effect of HIF-1alpha on tumor response to antiangiogenesis

描述（申请人提供）：肿瘤的发展依赖于肿瘤上皮细胞和肿瘤血管之间的动态平衡。因此，抗血管生成治疗是抑制肿瘤生长和发展的合理和有效的方法。血管内皮生长因子A （Vascular endothelial growth factor A， VEGFA或VEGF）是肿瘤血管生成中已被充分证实的显性生长因子，靶向VEGF治疗人类癌症的临床前景进一步证实了这一点。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重要作用。大量证据表明，HIF-1诱导缺氧反应中重要基因的表达，如抗凋亡、糖酵解、血管生成、细胞迁移和转移。然而，HIF-1a是否单独介导缺氧条件下的肿瘤存活尚不清楚；或者冗余通路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。越来越多的人关注有效的抗血管生成治疗是肿瘤反应性抵抗：由此导致的肿瘤内缺氧的增加可能会驱使细胞选择对脉管系统依赖性较低的细胞，而这些细胞反过来可能更恶性。虽然反应性抵抗被认为是由缺氧驱动的，但反应性抵抗是否由hif （HIF-1a和HIF-2B）介导仍有待确定。本提案的主要目的是确定HIF-1a在介导肿瘤对抗血管生成治疗的反应中的直接作用。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，使用人类癌细胞敲除技术开发了临床前模型系统。从这些研究中获得的见解应该有助于我们对癌症生物学的理解和抗血管生成治疗的合理组合。

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.