Selective blockade of tumor angiogenesis
Selective blockade of tumor angiogenesis
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DOI：
10.4161/cc.20374
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发表时间：
2012-06-15
期刊：
影响因子：
4.3
通讯作者：
Croix, Brad St.
中科院分区：
文献类型：
--
作者：
Chaudhary, Amit;Croix, Brad St.
阻断肿瘤血管生成是癌症治疗的一个重要目标，但临床批准的抗血管生成药物的功效有限且具有不良副作用，因此迫切需要寻找替代的血管生成调节剂。肿瘤内皮标志物 8 (TEM8) 是一种高度保守的细胞表面受体，在人类肿瘤血管系统中过度表达。小鼠中 Tem8 的基因破坏表明，TEM8 对于促进肿瘤血管生成和肿瘤生长很重要，但对于正常发育和伤口愈合却是可有可无的。通过营养或生长因子剥夺在培养的内皮细胞中诱导 TEM8 表明 TEM8 可能是肿瘤微环境应激激活的生存反应途径的一部分。在临床前研究中，针对 TEM8 胞外结构域的抗体抑制肿瘤血管生成并阻止多个人类肿瘤异种移植物的生长。抗 TEM8 抗体增强了其他抗血管生成剂、血管靶向剂和常规化疗剂的活性，并且没有表现出可检测到的毒性。因此，抗TEM8抗体提供了一种有前途的新工具，用于选择性阻断与癌症和可能的其他血管生成依赖性疾病相关的新血管形成。
Blocking tumor angiogenesis is an important goal of cancer therapy, but clinically approved anti-angiogenic agents suffer from limited efficacy and adverse side effects, fueling the need to identify alternative angiogenesis regulators. Tumor endothelial marker 8 (TEM8) is a highly conserved cell surface receptor overexpressed on human tumor vasculature. Genetic disruption of Tem8 in mice revealed that TEM8 is important for promoting tumor angiogenesis and tumor growth but dispensable for normal development and wound healing. The induction of TEM8 in cultured endothelial cells by nutrient or growth factor deprivation suggests that TEM8 may be part of a survival response pathway that is activated by tumor microenvironmental stress. In preclinical studies, antibodies targeted against the extracellular domain of TEM8 inhibited tumor angiogenesis and blocked the growth of multiple human tumor xenografts. Anti-TEM8 antibodies augmented the activity of other anti-angiogenic agents, vascular targeting agents and conventional chemotherapeutic agents and displayed no detectable toxicity. Thus, anti-TEM8 antibodies provide a promising new tool for selective blockade of neovascularization associated with cancer and possibly other angiogenesis-dependent diseases.