Role of Vessel Maturity in Antiangiogenic Drug Efficacy

描述(申请人提供)：肿瘤的生长依赖于血管生成，然而肿瘤对血管生成抑制剂的反应是不可预测的。我们认为支配肿瘤对这些药物的反应的一个主要变量是其血管系统的成熟状态。抗血管生成药物针对的是生长中的和新形成的血管，而已建立的血管不受影响。我们推测，与血管较不成熟的肿瘤相比，血管形成较多的肿瘤对抗血管生成药物的反应较差。 这项工作是从我们早期对脂肪组织的研究延伸出来的，表明血管成熟是组织重塑能力的决定因素。我们证明，一个相对不成熟的血管系统对于维持脂肪组织发育后的可塑性是必要的。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质量，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，将与荷瘤小鼠并行研究第二种血管生成依赖生长模型。脂肪组织和肿瘤一样，具有相当大的生长能力，血管系统相对不成熟，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、稳定的生长模式。比较这两种模型有望揭示血管成熟与组织重塑和对血管生成抑制剂的反应之间的共同机制。 我们将从分子(血管生成素/TiE系统)和细胞(周细胞)标记来表征血管成熟，并研究干扰这一参数对荷瘤小鼠和肥胖小鼠组织对血管生成抑制剂敏感性的影响。了解这种关系可能使血管生成抑制剂能够更可预测、更有效地用于癌症的治疗。

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.