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

癌症的进展依赖于血管生成。抗血管生成(节律性或低剂量)化疗是一种通过给予低浓度的传统细胞毒药物而不需要休息时间来优化化疗效果的策略。我们和其他人已经证明，一种内源性血管生成抑制物，血栓反应蛋白-1(TSP-1)，有助于低剂量环磷酰胺介导的肿瘤微环境中内皮细胞的凋亡。在这里，我们调查了内源性内皮抑素是否在低剂量化疗中作为血管生成抑制物。低剂量紫杉醇治疗主要诱导Lewis肺癌细胞(LLC)内皮抑素的表达，但对B16F10黑色素瘤细胞(B16F10)、内皮细胞或成纤维细胞无明显影响。低剂量紫杉醇治疗还上调了LLC荷瘤小鼠循环中内皮抑素的产生，并进一步降低了平均肿瘤体积和血管密度。相比之下，sFlt-L、TSP-1和Tumstatin在同一环境中没有受到影响。小鼠体内缺乏内皮抑素导致低剂量紫杉醇抑制肿瘤生长的能力减弱。此外，低氧可阻断紫杉醇诱导的内皮抑素表达上调，而阻断缺氧诱导因子-1α可显著增加内皮抑素的表达，提示肿瘤细胞内源性内皮抑素的产生受缺氧诱导因子-1α的调控。这些研究表明，内皮抑素是低剂量紫杉醇抗血管生成作用的关键介质。

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.