Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy.
Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy.
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DOI：
10.18632/oncotarget.11748
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发表时间：
2016-10-04
期刊：
影响因子：
--
通讯作者：
Ryeom S
中科院分区：
文献类型：
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作者：
Schadler KL;Thomas NJ;Galie PA;Bhang DH;Roby KC;Addai P;Till JE;Sturgeon K;Zaslavsky A;Chen CS;Ryeom S
针对肿瘤血管系统的靶向治疗与化疗联合使用，以改善肿瘤血管正常化后的药物递送和疗效。肿瘤血管高度紊乱，血流中断阻碍药物递送至癌细胞。虽然药物抗血管生成治疗可以重塑和正常化肿瘤血管，但有效性窗口有限，并且这些药物与严重的副作用相关，需要血管正常化的替代方案。最近，适度的有氧运动已被证明可以诱导小鼠模型的血管正常化。在这里，我们提供了一个机械的解释，运动诱导肿瘤血管正常化。切应力是血流对内皮细胞施加的机械刺激，调节血管的完整性。通过有氧运动增加血管切应力可以改变和重塑正常组织中的血管。我们在小鼠模型中的数据表明，内皮细胞中钙调神经磷酸酶-NFAT-TSP 1信号传导的激活在运动诱导的切应力介导的肿瘤血管重塑中起关键作用。我们发现，通过改善肿瘤血管正常化后的化疗输送，适度的有氧运动联合化疗比单独化疗能显著降低肿瘤生长。我们的工作表明，有氧运动的血管正常化作用可以是一种有效的化疗辅助。
Targeted therapies aimed at tumor vasculature are utilized in combination with chemotherapy to improve drug delivery and efficacy after tumor vascular normalization. Tumor vessels are highly disorganized with disrupted blood flow impeding drug delivery to cancer cells. Although pharmacologic anti-angiogenic therapy can remodel and normalize tumor vessels, there is a limited window of efficacy and these drugs are associated with severe side effects necessitating alternatives for vascular normalization. Recently, moderate aerobic exercise has been shown to induce vascular normalization in mouse models. Here, we provide a mechanistic explanation for the tumor vascular normalization induced by exercise. Shear stress, the mechanical stimuli exerted on endothelial cells by blood flow, modulates vascular integrity. Increasing vascular shear stress through aerobic exercise can alter and remodel blood vessels in normal tissues. Our data in mouse models indicate that activation of calcineurin-NFAT-TSP1 signaling in endothelial cells plays a critical role in exercise-induced shear stress mediated tumor vessel remodeling. We show that moderate aerobic exercise with chemotherapy caused a significantly greater decrease in tumor growth than chemotherapy alone through improved chemotherapy delivery after tumor vascular normalization. Our work suggests that the vascular normalizing effects of aerobic exercise can be an effective chemotherapy adjuvant.