Role of Vessel Maturity in Antiangiogenic Drug Efficacy

血管成熟度在抗血管生成药物疗效中的作用

• 批准号: 6777785
• 负责人: MARIA A RUPNICK
• 金额: $ 14.26万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-07 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6777785
• 关键词: SCID mouse; adipose tissue; angiogenesis; angiogenesis inhibitors; angiopoietins; angiostatins; antineoplastics; cell line; connective tissue growth factor; drug administration rate /duration; drug screening /evaluation; genetically modified animals; laboratory mouse; neoplasm /cancer blood supply; neoplasm /cancer classification /staging; neoplastic growth; pathologic process; pharmacokinetics; regeneration; tetracyclines; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Tumor growth is angiogenesis dependent yet tumor responses to angiogenesis inhibitors vary unpredictably. We propose that a dominant variable governing a tumor's response to these drugs is the maturation state of its vasculature. Anti-angiogenic agents target growing and newly formed vessels, while established ones are unaffected. We hypothesize that tumors with a greater proportion of established vessels may be less responsive to anti-angiogenic agents than those with more immature vessels. This work extends from our earlier studies in adipose tissue showing that vascular maturation is a determinant of a tissue's capacity to remodel. We demonstrated that a relatively immature vasculature is necessary to preserve adipose tissue plasticity after development. We further found that angiogenesis inhibitors selectively reduce adipose tissue mass in obese mice, while other organs are unaffected. We propose that vascular maturation is a regulator of a tissue's susceptibility to antiangiogenic agents has potential prognostic and therapeutic implications for the use of these agents in cancer therapy. Recognizing that tumors encompass highly diverse, genetically unstable pathologies, a second model of angiogenesis-dependent growth will be studied in parallel with tumor bearing mice. Adipose tissue, like tumors, has a substantial growth capacity, relatively immature vasculature, and is susceptible to angiogenesis inhibitors. However, it is a non-transformed, normal tissue with tightly regulated, stable growth patterns. Comparing both models is expected to reveal common mechanism relating vessel maturation with tissue remodeling and responses to angiogenesis inhibitors. We will characterize vascular maturation in terms of molecular (angiopoietin/tie system) and cellular (pericytes) markers and examine the effect of perturbing this parameter on tissue susceptibility to angiogenesis inhibitors in tumor bearing mice and in obese mice. Understanding this relationship may enable a more predictable, effective use of angiogenesis inhibitors for the treatment of cancers.

描述（由申请人提供）：肿瘤生长依赖于血管生成，但肿瘤对血管生成抑制剂的反应变化不可预测。我们认为，控制肿瘤对这些药物反应的主要变量是其脉管系统的成熟状态。抗血管生成剂针对正在生长的血管和新形成的血管，而已形成的血管则不受影响。我们假设，与具有较多未成熟血管的肿瘤相比，具有较大比例已建立血管的肿瘤对抗血管生成药物的反应可能较低。 这项工作延续了我们早期对脂肪组织的研究，表明血管成熟是组织重塑能力的决定因素。我们证明，相对不成熟的脉管系统对于在发育后保持脂肪组织的可塑性是必要的。我们进一步发现，血管生成抑制剂选择性地减少肥胖小鼠的脂肪组织量，而其他器官不受影响。我们认为，血管成熟是组织对抗血管生成药物敏感性的调节因素，对于这些药物在癌症治疗中的使用具有潜在的预后和治疗意义。 认识到肿瘤包含高度多样化、遗传不稳定的病理学，我们将与荷瘤小鼠同时研究血管生成依赖性生长的第二种模型。脂肪组织与肿瘤一样，具有显着的生长能力、相对不成熟的脉管系统，并且对血管生成抑制剂敏感。然而，它是一种未转化的正常组织，具有严格调控的稳定生长模式。比较这两种模型有望揭示血管成熟与组织重塑以及对血​​管生成抑制剂的反应相关的共同机制。 我们将根据分子（血管生成素/连接系统）和细胞（周细胞）标记来表征血管成熟，并检查扰乱该参数对荷瘤小鼠和肥胖小鼠中组织对血管生成抑制剂的敏感性的影响。了解这种关系可能有助于更可预测、更有效地使用血管生成抑制剂来治疗癌症。