FLK1 SIGNALING PROTECTS TUMOR VASCULATURE FROM RADIATION

FLK1 信号传导保护肿瘤血管免受辐射

• 批准号: 6498007
• 负责人: DENNIS E HALLAHAN
• 金额: $ 25.55万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-12 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6498007
• 关键词: Adenoviridae; BCL2 gene /protein; apoptosis; astrocytoma; athymic mouse; biological signal transduction; cell migration; cell proliferation; cysteine endopeptidases; enzyme activity; enzyme inhibitors; fluorescence microscopy; growth factor receptors; inhibitor /antagonist; ionizing radiation; melanoma; neoplasm /cancer blood supply; neoplasm /cancer radiation therapy; phosphatidylinositol 3 kinase; protein kinase; radiation resistance; transfection /expression vector; vascular endothelial growth factors; vascular endothelium; western blottings

DESCRIPTION: (Applicant's Abstract) Tumor blood flow increases after x-irradiation. Similarly, the tumor vascular window model shows that tumor blood vessels are resistant to radiation as compared to blood vessels in more sensitive tumors. The applicant proposes that the signal transduction pathways required for endothelial survival and repair are targets to improve the therapeutic effects of ionizing radiation. The survival pathway activated by angiogenic ligands, such as VEGF and angiopoietein-1, mediate signal transduction through PI3 kinase and protein kinase B (Akt). Akt in turn, inhibits programmed cell death (apoptosis) by increased expression of Bcl-2 and Bcl-XL and through phosphorylation of Bad. His preliminary data show that inhibition of Flk-1 or PI3 kinase blocks the survival pathway and allows for radiation-induced apoptosis. He has focused on the VEGF R2 (Flk-1) receptor tyrosine kinase by use of specific inhibitors of Flk-1 (soluble Flk-1 and SU5416). Flk-1 inhibition enhanced radiation-induced apoptosis and HUVEC and 3B11 endothelial cells. Likewise, inhibitors of PI3 kinase block the survival pathway and enhance radiation-induced apoptosis in endothelial cells. To determine whether Flk-1 inhibition enhances the radiation effect in tumor vascular endothelium, he utilized the tumor vascular window and tumor blood flow analysis by Doppler ultrasound. The applicant's preliminary data show that both soluble Flk-1 and SU5416 block the resistance phenotype in vascular endothelium in blood vessels of all tumor types. Flk-1 also activates an endothelial repair pathway that consists of proliferation, migration and recruitment of endothelial progenitor cells. He, therefore, studied recruitment of endothelial progenitor cells into irradiated tumors. This showed that Flk-1+ endothelial progenitors extravasate from the tumor microvasculature into the perivascular space of irradiated tumors. He hypothesizes that the Flk-1 receptor is required for this repair process and that Flk-1 inhibition will improve radiation responsiveness in tumors. In the proposed studies, the applicant will determine the mechanisms of Flk-1-mediated survival in irradiated tumor blood vessels. He will study signal transduction through PI3 kinase and Akt. He will also determine whether this signal transduction pathway inhibits radiation-induced apoptosis by increased expression of Bcl-2 of Bcl-XL and phosphorylation of Bad. He will determine whether the Flk-1 receptor is required for repair of the tumor microvascular endothelium. Each of these findings will be applied to Specific Aim 4, in which he will optimize the administration of Flk-1 inhibitors to improve the tumor control by ionizing radiation.

描述：（申请人的摘要）肿瘤血流在 X-radiation。同样，肿瘤血管窗口模型表明肿瘤 与血管相比，血管对辐射具有抵抗力 敏感肿瘤。申请人提出信号转导途径 内皮生存和维修所需的目标是改善 电离辐射的治疗作用。生存途径被激活 血管生成配体（例如VEGF和Angiopoietein-1）介导信号 通过PI3激酶和蛋白激酶B（AKT）的转导。又依次 通过增加Bcl-2和 Bcl-XL并通过不良的磷酸化。他的初步数据表明 抑制FLK-1或PI3激酶会阻止生存途径并允许 辐射引起的凋亡。他专注于VEGF R2（FLK-1）受体 酪氨酸激酶通过使用FLK-1的特定抑制剂（可溶性​​FLK-1和 SU5416）。 FLK-1抑制作用增强了辐射诱导的凋亡和HUVEC，以及 3B11内皮细胞。同样，PI3激酶的抑制剂阻止了生存 途径并增强辐射诱导的内皮细胞凋亡。到 确定FLK-1抑制是否会增强肿瘤的辐射效应 血管内皮，他利用肿瘤血管窗口和肿瘤血液 多普勒超声分析的流量分析。申请人的初步数据表明 可溶性FLK-1和SU5416都阻止了血管中的电阻表型 所有肿瘤类型的血管内皮。 FLK-1还激活 内皮修复途径包括扩散，迁移和 内皮祖细胞的募集。因此，他研究了招聘 内皮祖细胞成辐照肿瘤。这表明FLK-1+ 内皮祖细胞从肿瘤微举行 辐照肿瘤的血管周空间。他假设FLK-1 此修复过程需要受体，并且FLK-1抑制作用将 改善肿瘤的辐射反应能力。在拟议的研究中， 申请人将确定FLK-1介导的生存的机制 辐照肿瘤血管。他将研究通过PI3转导信号 激酶和Akt。他还将确定该信号转导途径是否 通过增加Bcl-2的Bcl-XL表达来抑制辐射诱导的凋亡 和不良的磷酸化。他将确定FLK-1受体是否是 修复肿瘤微血管内皮所必需的。每个 调查结果将应用于特定目标4，他将在其中优化 通过电离来施用FLK-1抑制剂以改善肿瘤控制 辐射。