Schaffhauser Birgit, Veikkola Tanja, Strittmatter Karin, Antoniadis Helena, Alitalo Kari, Christofori Gerhard
Department of Clinical-Biological Sciences, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
J Leukoc Biol. 2006 Oct;80(4):669-76. doi: 10.1189/jlb.1105644. Epub 2006 Jun 22.
Many previous reports have demonstrated that systemic administration of endostatin (ES), a proteolytic cleavage product of collagen type XVIII and an endogenous angiogenesis inhibitor, represses tumor angiogenesis in different preclinical tumor models with varying efficacy. For example, systemic delivery of recombinant ES to rat insulin promoter 1 (Rip1)T-antigen 2 (Tag2)-transgenic mice, a mouse model of pancreatic beta-cell carcinogenesis, has repressed tumor angiogenesis efficiently and with it, tumor growth. Here, we report that the transgenic expression of ES in Rip1ES-transgenic mice only interferes moderately with tumor growth in Rip1Tag2;Rip1ES double-transgenic mice. Tumor incidence is not reduced by the local expression of ES, and tumor outgrowth and progression to tumor malignancy are only retarded slightly. A significant effect of local ES expression on tumor angiogenesis is only apparent during the early stages of tumor development, where less angiogenic hyperplastic lesions are observed. Although efficiently produced and secreted by transgenic beta cells, locally expressed ES appears to be sequestered in the microenvironment, and its systemic levels are not increased. The results indicate that the antiangiogenic functions of ES critically depend on the mode of delivery and the site of expression: although its systemic application represses tumor angiogenesis and tumor growth efficiently, locally expressed ES appears to be less effective, and hence, additional mechanisms of solubilization or activation of latent ES seem to be required. These results have important implications about the modes of delivery used in antiangiogenic, therapeutic strategies, which are based on the antiangiogenic activities of ES.
许多先前的报告表明，内皮抑素（ES）是 XVIII 型胶原蛋白的蛋白水解裂解产物，也是一种内源性血管生成抑制剂，全身给药后，在不同的临床前肿瘤模型中以不同的疗效抑制肿瘤血管生成。例如，将重组 ES 全身递送至大鼠胰岛素启动子 1（Rip1）T 抗原 2（Tag2）转基因小鼠（一种胰腺β细胞癌变的小鼠模型），可有效抑制肿瘤血管生成，并随之抑制肿瘤生长。在此，我们报告在 Rip1ES 转基因小鼠中 ES 的转基因表达仅适度干扰 Rip1Tag2;Rip1ES 双转基因小鼠的肿瘤生长。ES 的局部表达并未降低肿瘤发生率，肿瘤生长及向肿瘤恶性程度的进展仅略有延迟。ES 局部表达对肿瘤血管生成的显著影响仅在肿瘤发展的早期阶段明显，此时观察到的血管生成性增生性病变较少。尽管转基因β细胞能有效产生和分泌局部表达的 ES，但它似乎被隔离在微环境中，其全身水平并未升高。结果表明，ES 的抗血管生成功能严重依赖于递送方式和表达位点：尽管其全身应用能有效抑制肿瘤血管生成和肿瘤生长，但局部表达的 ES 似乎效果较差，因此，似乎需要其他溶解或激活潜在 ES 的机制。这些结果对于基于 ES 抗血管生成活性的抗血管生成治疗策略中使用的递送方式具有重要意义。
