Role of Vessel Maturity in Antiangiogenic Drug Efficacy

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，一个主导变量控制肿瘤的反应，这些药物是成熟状态的血管。抗血管生成剂靶向生长和新形成的血管，而已建立的血管不受影响。我们推测，具有较大比例的已建立血管的肿瘤可能比具有更多未成熟血管的肿瘤对抗血管生成剂的反应更低。 这项工作从我们早期的脂肪组织研究中延伸出来，表明血管成熟是组织重塑能力的决定因素。我们证明了一个相对不成熟的血管系统是必要的，以保持脂肪组织的可塑性后发展。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子，对于这些药物在癌症治疗中的应用具有潜在的预后和治疗意义。 认识到肿瘤包含高度多样性、遗传不稳定的病理，将与荷瘤小鼠平行研究血管生成依赖性生长的第二个模型。脂肪组织，如肿瘤，具有相当大的生长能力，相对不成熟的脉管系统，并且对血管生成抑制剂敏感。然而，它是一种非转化的正常组织，具有严格调控的稳定生长模式。比较这两种模型，预计将揭示共同的机制，血管成熟与组织重塑和血管生成抑制剂的反应。 我们将表征血管成熟的分子（血管生成素/领带系统）和细胞（周细胞）标志物，并检查在荷瘤小鼠和肥胖小鼠的血管生成抑制剂的组织易感性扰动这一参数的影响。了解这种关系可能使更可预测的，有效地使用血管生成抑制剂治疗癌症。

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.