Endostatin contributes to low-dose paclitaxel-mediated tumor growth and angiogenesis suppression

内皮抑素有助于低剂量紫杉醇介导的肿瘤生长和血管生成抑制

基本信息

批准号：
18590364
负责人：
HAMANO Yuki
金额：
$ 2.46万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590364/
关键词：
Endostatin Low-dose chemotherapy HIF-1α Paclitaxel Metastatic tumor Endogenous angiogenesis inhibitor Angiogenesis

项目摘要

Progression of cancer is dependent on angiogenesis. Anti-angiogenic (metronomic or low-dose) chemotherapy is a strategy for optimizing the effects of chemotherapeutics by administrating traditional cytotoxic drugs at lower concentrations without a rest period. We and others have shown that an endogenous angiogenesis inhibitor, thrombospondin-1 (TSP-1), contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis in the tumor microenvironment. Here, we investigate whether endogenous endostatin serves as an angiogenic inhibitor in low-dose chemotherapy. Low-dose paclitaxel treatment predominantly induced the expression of endostatin in Lewis lung carcinoma cells (LLC), but not in B16F10 melanoma cells (B16F10), endothelial cells or fibroblasts. Low-dose paclitaxel treatment also upregulated the production of endostatin in the circulation of LLC-bearing mice and further reduced the mean tumor volume and blood vessel density. In contrast, sFlt-l, TSP-1 and tumstatin were not affected in the same setting. Lack of endostatin in mice led to the diminished capacity of low-dose paclitaxel to suppress tumor growth. In addition, hypoxia blocked the paclitaxel-mediated upregulation of endostatin while the disruption of HIF-1α significantly increased the expression of endostatin, suggesting that the production of endogenous endostatin is controlled by HIF-1α in the tumor cells. Theses studies demonstrate that endostatin is a key mediator of anti-angiogenic effects observed with low-dose paclitaxel treatment.

癌症的进展取决于血管生成（节律性或低剂量）化疗是一种通过在不休息的情况下施用较低浓度的传统细胞毒性药物来优化化疗效果的策略。抑制剂血小板反应蛋白-1 (TSP-1) 有助于肿瘤微环境中低剂量环磷酰胺介导的内皮细胞凋亡。内源性内皮抑素在低剂量化疗中作为血管生成抑制剂，低剂量紫杉醇治疗主要诱导Lewis肺癌细胞（LLC）中内皮抑素的表达，但在B16F10黑色素瘤细胞（B16F10）、内皮细胞或成纤维细胞中不表达。紫杉醇治疗剂量还上调了 LLC 荷瘤小鼠循环中内皮抑素的产生，并进一步减少了平均肿瘤体积和血液相比之下，sFlt-1、TSP-1 和肿瘤抑素在相同环境中不受影响，导致低剂量紫杉醇抑制肿瘤生长的能力减弱。介导的内皮抑素上调，而 HIF-1α 的破坏显着增加了内皮抑素的表达，表明内源性内皮抑素的产生是由 HIF-1α 控制的。这些研究表明，内皮抑素是低剂量紫杉醇治疗中观察到的抗血管生成作用的关键介质。