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

基本信息

批准号：
6892930
负责人：
MARIA A RUPNICK
金额：
$ 14.3万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-07 至 2007-04-30
项目状态：
已结题

项目摘要

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）：肿瘤生长取决于血管生成，但肿瘤对血管生成抑制剂的反应异常变化。我们建议，管理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。抗血管生成剂靶向生长和新形成的血管，而已建立的血管则不受影响。我们假设比具有更多不成熟血管的肿瘤对抗血管生成剂的反应较高，对抗血管生成剂的反应较低。这项工作源于我们早期在脂肪组织的研究，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保留发育后的脂肪组织可塑性是必不可少的。我们进一步发现，血管生成抑制剂有选择地减少肥胖小鼠的脂肪组织量，而其他器官不受影响。我们建议血管成熟是组织对抗血管生成剂的敏感性的调节剂，对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。认识到肿瘤包括高度多样化的遗传性不稳定病理，第二种模型的血管生成依赖性生长将与肿瘤轴承小鼠并联研究。脂肪组织如肿瘤，具有实质性的生长能力，相对不成熟的脉管系统，并且容易受到血管生成抑制剂的影响。但是，它是一种未转化的正常组织，具有严格调节的稳定生长模式。比较两种模型都可以揭示有关血管成熟与组织重塑的共同机制，并对血管生成抑制剂的反应。我们将以分子（血管生成素/TIE系统）和细胞（周细胞）标记来表征血管成熟，并检查该参数对肿瘤轴承小鼠和肥胖小鼠的血管生成抑制剂的组织敏感性对血管生成抑制剂的影响。了解这种关系可能会使更有效的，有效地使用血管生成抑制剂来治疗癌症。