Normalization of the vasculature for treatment of cancer and other diseases.
Normalization of the vasculature for treatment of cancer and other diseases.
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DOI：
10.1152/physrev.00038.2010
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发表时间：
2011-07
影响因子：
33.6
通讯作者：
Jain RK
中科院分区：
文献类型：
--
作者：
Goel S;Duda DG;Xu L;Munn LL;Boucher Y;Fukumura D;Jain RK
新血管形成（血管生成）是胚胎发育、正常生长和组织修复的重要生理过程。血管生成在分子水平上受到严格调控。血管生成的失调发生在各种病理学中，并且是癌症的标志之一。肿瘤内促血管生成信号和抗血管生成信号的不平衡产生异常的血管网络，其特征在于扩张的、曲折的和高渗透性的血管。这些血管异常的生理后果包括肿瘤血流和氧合的时间和空间异质性以及肿瘤间质流体压力增加。这些异常和由此产生的微环境助长了肿瘤的进展，也导致化疗、放疗和免疫治疗的疗效降低。随着血管内皮生长因子（VEGF）作为肿瘤血管生成的主要驱动因素的发现，努力集中在旨在抑制VEGF活性的新疗法上，其目标是通过饥饿使肿瘤消退。不幸的是，在实体瘤患者中进行的抗VEGF单药治疗的临床试验在很大程度上是阴性的。有趣的是，与单纯化疗相比，抗VEGF治疗与常规化疗的联合治疗提高了癌症患者的生存率。这些看似矛盾的结果可以通过抗VEGF治疗使肿瘤血管“正常化”来解释。临床前研究已经表明，抗VEGF治疗将肿瘤血管系统改变为更“成熟”或“正常”的表型。这种“血管正常化”的特征在于高渗透性的减弱、血管周细胞覆盖的增加、更正常的基底膜以及由此产生的肿瘤缺氧和间质液压力的降低。这些又可以导致肿瘤微环境的代谢特征、外源性施用的治疗剂的递送和功效、放射疗法和效应免疫细胞的功效的改善，以及由肿瘤脱落到小鼠循环中的转移性细胞的数量的减少。这些发现与抗VEGF药物在各种实体瘤患者中的临床试验数据一致。最近，遗传学和药理学方法已经开始解开血管正常化的一些其他关键调节因子，例如调节组织氧传感（PHD 2）和血管成熟（PDGFRβ，RGS 5，Ang 1/2，TGF-β）的蛋白质。在这里，我们回顾了肿瘤血管生成的病理生理学，血管正常化的分子基础和功能后果，以及对癌症和非恶性疾病治疗的影响。
New vessel formation (angiogenesis) is an essential physiological process for embryologic development, normal growth, and tissue repair. Angiogenesis is tightly regulated at the molecular level. Dysregulation of angiogenesis occurs in various pathologies and is one of the hallmarks of cancer. The imbalance of pro- and anti-angiogenic signaling within tumors creates an abnormal vascular network that is characterized by dilated, tortuous, and hyperpermeable vessels. The physiological consequences of these vascular abnormalities include temporal and spatial heterogeneity in tumor blood flow and oxygenation and increased tumor interstitial fluid pressure. These abnormalities and the resultant microenvironment fuel tumor progression, and also lead to a reduction in the efficacy of chemotherapy, radiotherapy, and immunotherapy. With the discovery of vascular endothelial growth factor (VEGF) as a major driver of tumor angiogenesis, efforts have focused on novel therapeutics aimed at inhibiting VEGF activity, with the goal of regressing tumors by starvation. Unfortunately, clinical trials of anti-VEGF monotherapy in patients with solid tumors have been largely negative. Intriguingly, the combination of anti-VEGF therapy with conventional chemotherapy has improved survival in cancer patients compared with chemotherapy alone. These seemingly paradoxical results could be explained by a “normalization” of the tumor vasculature by anti-VEGF therapy. Preclinical studies have shown that anti-VEGF therapy changes tumor vasculature towards a more “mature” or “normal” phenotype. This “vascular normalization” is characterized by attenuation of hyperpermeability, increased vascular pericyte coverage, a more normal basement membrane, and a resultant reduction in tumor hypoxia and interstitial fluid pressure. These in turn can lead to an improvement in the metabolic profile of the tumor microenvironment, the delivery and efficacy of exogenously administered therapeutics, the efficacy of radiotherapy and of effector immune cells, and a reduction in number of metastatic cells shed by tumors into circulation in mice. These findings are consistent with data from clinical trials of anti-VEGF agents in patients with various solid tumors. More recently, genetic and pharmacological approaches have begun to unravel some other key regulators of vascular normalization such as proteins that regulate tissue oxygen sensing (PHD2) and vessel maturation (PDGFRβ, RGS5, Ang1/2, TGF-β). Here, we review the pathophysiology of tumor angiogenesis, the molecular underpinnings and functional consequences of vascular normalization, and the implications for treatment of cancer and nonmalignant diseases.
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影响因子：
6
作者：
Avraham, Tomer;Daluvoy, Sanjay;Mehrara, Babak J.
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KESHET, E
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作者：
Bondjers, C;Kalén, M;Betsholtz, C
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Betsholtz, C