Vasculogenesis in Ewing's Sarcoma: useintherapy

尤文氏肉瘤的血管发生：在治疗中的应用

• 批准号: 6914939
• 负责人: Eugenie S Kleinerman
• 金额: $ 24.76万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6914939
• 关键词: CD34 molecule; Ewing' s tumor; SCID mouse; angiogenesis; athymic mouse; bone marrow; cell cycle; cell differentiation; cell migration; chemotaxis; cholecalciferol; clinical research; cord blood; flow cytometry; gene delivery system; gene therapy; genetically modified animals; hematopoietic stem cells; human tissue; immunocytochemistry; interleukin 12; laboratory mouse; neoplastic growth; nonhuman therapy evaluation; small interfering RNA; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Despite multiple changes in the chemotherapeutic approach for Ewing's sarcoma, the 2 year disease-free survival remains at 40-50% depending on disease site. Better understanding of the tumor biology may uncover therapeutic approaches. Using a nude mouse model, we demonstrated that Ewing's sarcoma cells overexpress VEGF and that bone marrow stem cells contribute to the development of new tumor vasculature as the tumor grows (a process known as vasculogenesis as opposed to angiogenesis). Approximately 10% of the new tumor vessels could be attributed to vasculogenesis. We further demonstrated the chemotactic capability of VEGF for bone marrow cells both in vitro (using Boyden Chambers) and in vivo (using matrigel-VEGF plugs). Together these data suggest that bone marrow cells travel to the tumor area in response to VEGF and subsequently contribute to the expansion of the tumor vasculature that is required to support the growing tumor. Our goal is to determine whether VEGF is the chemotactic stimulus, if suppressing VEGF has an impact on bone marrow cell migration and subsequent tumor vasculogenesis, and finally whether these bone marrow cells can be modified to deliver genes to the tumor area. We propose to (1) define the bone marrow cell subpopulations that contribute to this vasculogenesis process. (2) Determine whether cell division of migrated bone marrow cells contributes to vasculogenesis. (3) Determine whether tumor VEGF165 production influences tumor vasculogenesis. This will be done by inhibiting VEGF165 by siRNA. (4) Determine whether CD34+ (or mesenchymal cells as an alternative) can be used to deliver genes to the tumor area. Understanding the biology and the role that vasculogenesis plays in the development of Ewing's sarcoma may provide new therapeutic targets. Our goal is to identify whether VEGF165 is the chemotactic signal, to determine whether interfering with VEGF165 has an impact on the migration of bone marrow cells and explore whether these cells can be used to deliver genes to the tumor area.

描述（由申请人提供）：尽管尤文氏肉瘤的化疗方法发生了多次变化，但根据疾病部位的不同，2 年无病生存率仍保持在 40-50%。更好地了解肿瘤生物学可能会发现治疗方法。使用裸鼠模型，我们证明尤文氏肉瘤细胞过度表达 VEGF，并且随着肿瘤生长，骨髓干细胞有助于新肿瘤脉管系统的发育（这一过程称为血管生成，而不是血管生成）。大约 10% 的新肿瘤血管可归因于血管发生。我们在体外（使用 Boyden Chambers）和体内（使用基质胶-VEGF 塞）进一步证明了 VEGF 对骨髓细胞的趋化能力。这些数据共同表明，骨髓细胞响应 VEGF 移动到肿瘤区域，随后有助于支持肿瘤生长所需的肿瘤脉管系统的扩张。我们的目标是确定 VEGF 是否是趋化刺激物，抑制 VEGF 是否对骨髓细胞迁移和随后的肿瘤血管生成产生影响，以及最终是否可以修改这些骨髓细胞以将基因传递到肿瘤区域。我们建议（1）定义有助于这种血管生成过程的骨髓细胞亚群。 (2)确定迁移的骨髓细胞的细胞分裂是否有助于血管生成。 (3)确定肿瘤VEGF165的产生是否影响肿瘤血管生成。这将通过 siRNA 抑制 VEGF165 来完成。 (4) 确定是否可以使用CD34+（或间充质细胞作为替代）将基因递送至肿瘤区域。了解血管生成在尤文氏肉瘤发展中的生物学和作用可能会提供新的治疗靶点。我们的目标是鉴定VEGF165是否是趋化信号，确定干扰VEGF165是否对骨髓细胞的迁移产生影响，并探索这些细胞是否可以用于将基因传递到肿瘤区域。