Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy.
Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy.
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DOI：
10.1111/cas.12836
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发表时间：
2016-01
期刊：
影响因子：
5.7
通讯作者：
Takakura N
中科院分区：
文献类型：
--
作者：
Zhang L;Takara K;Yamakawa D;Kidoya H;Takakura N
抗血管生成剂可使肿瘤血管结构短暂正常化并改善血管功能，从而为增强化疗或放疗的疗效提供了机会之窗。目前，在抗血管生成治疗期间，没有可靠的预测因子或标志物反映该血管正常化窗口。Apelin是一种易于测量的分泌蛋白，其表达受缺氧调节，并且在肿瘤进展中具有充分描述的作用。在这里，我们表明，爱帕琳蛋白可以用作抗血管生成治疗期间血管正常化窗口的标记物。小鼠皮下接种用单次注射贝伐单抗（一种中和血管内皮生长因子的mAb）处理接种结肠腺癌细胞系HT 29产生的肿瘤。在用贝伐单抗治疗后的四个不同时间（第1、3、5和8天）测定肿瘤生长、血管密度、周细胞覆盖、肿瘤缺氧和小分子递送。贝伐单抗治疗后肿瘤生长和血管密度显著降低，这也显著增加了肿瘤血管成熟度，并改善了第3天至第5天之间的肿瘤缺氧和小分子递送。这些效应在第8天减弱，表明在该模型中贝伐珠单抗治疗期间，血管正常化的时间窗在第3天和第5天之间打开。在治疗后第5天，爱帕琳mRNA表达和血浆爱帕琳水平一过性降低，与血管正常化一致。因此，爱帕琳肽是抗血管生成治疗期间血管正常化窗口的潜在指标。
Antiangiogenic agents transiently normalize tumor vessel structure and improve vessel function, thereby providing a window of opportunity for enhancing the efficacy of chemotherapy or radiotherapy. Currently, there are no reliable predictors or markers reflecting this vessel normalization window during antiangiogenic therapy. Apelin, the expression of which is regulated by hypoxia, and which has well‐described roles in tumor progression, is an easily measured secreted protein. Here, we show that apelin can be used as a marker for the vessel normalization window during antiangiogenic therapy. Mice bearing s.c. tumors resulting from inoculation of the colon adenocarcinoma cell line HT29 were treated with a single injection of bevacizumab, a mAb neutralizing vascular endothelial growth factor. Tumor growth, vessel density, pericyte coverage, tumor hypoxia, and small molecule delivery were determined at four different times after treatment with bevacizumab (days 1, 3, 5, and 8). Tumor growth and vessel density were significantly reduced after bevacizumab treatment, which also significantly increased tumor vessel maturity, and improved tumor hypoxia and small molecule delivery between days 3 and 5. These effects abated by day 8, suggesting that a time window for vessel normalization was opened between days 3 and 5 during bevacizumab treatment in this model. Apelin mRNA expression and plasma apelin levels decreased transiently at day 5 post‐treatment, coinciding with vessel normalization. Thus, apelin is a potential indicator of the vessel normalization window during antiangiogenic therapy.