Tumor vasculature is innately dysfunctional. Poorly functional tumor vessels inefficiently deliver chemotherapy to tumor cells; vessel hyper‐permeability promotes chemotherapy delivery primarily to a tumor's periphery. Here, we identify a method for enhancing chemotherapy efficacy in Ewing sarcoma (ES) in mice by modulating tumor vessel permeability. Vessel permeability is partially controlled by the G protein‐coupled Sphinosine‐1‐phosphate receptors 1 and 2 (S1PR1 and S1PR2) on endothelial cells. S1PR1 promotes endothelial cell junction integrity while S1PR2 destabilizes it. We hypothesize that an imbalance of S1PR1:S1PR2 is partially responsible for the dysfunctional vascular phenotype characteristic of ES and that by altering the balance in favor of S1PR1, ES vessel hyper‐permeability can be reversed. In our study, we demonstrate that pharmacologic activation of S1PR1 by SEW2871 or inhibition of S1PR2 by JTE‐013 caused more organized, mature and functional tumor vessels. Importantly, S1PR1 activation or S1PR2 inhibition improved antitumor efficacy. Our data suggests that pharmacologic targeting of S1PR1 and S1PR2 may be a useful adjuvant to standard chemotherapy for ES patients.

中文翻译：

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调节鞘氨醇-1-磷酸受体以改善针对尤因肉瘤的化学疗法功效。

肿瘤脉管系统固有地功能失调。功能不良的肿瘤血管无法有效地将化学疗法传递给肿瘤细胞；血管通透性过高主要促进化学疗法向肿瘤周围的传递。在这里，我们确定了一种通过调节肿瘤血管通透性来增强小鼠尤文氏肉瘤（ES）化疗疗效的方法。血管渗透性部分受内皮细胞上G蛋白偶联的Sphinosine-1-磷酸盐受体1和2（S1PR1和S1PR2）控制。S1PR1促进内皮细胞连接完整性，而S1PR2使其不稳定。我们假设S1PR1：S1PR2的失衡是ES血管功能异常的部分原因，并且通过改变平衡以利于S1PR1，可以逆转ES血管的高通透性。在我们的研究中 我们证明SEW2871对S1PR1的药理激活或JTE-013对S1PR2的抑制引起更组织，成熟和功能性的肿瘤血管。重要的是，S1PR1激活或S1PR2抑制可提高抗肿瘤功效。我们的数据表明，S1PR1和S1PR2的药理靶向可能是ES患者标准化疗的有用辅助剂。