Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, Haartmaninkatu 8 (PO Box 63), FI-00014 University of Helsinki, Helsinki, Finland.
J Natl Cancer Inst. 2012 Mar 21;104(6):461-75. doi: 10.1093/jnci/djs009. Epub 2012 Feb 17.
Angiopoietin-2 (Ang2), a ligand for endothelial TEK (Tie2) tyrosine kinase receptor, is induced in hypoxic endothelial cells of tumors, where it promotes tumor angiogenesis and growth. However, the effects of Ang2 on tumor lymphangiogenesis and metastasis are poorly characterized.
We addressed the effect of Ang2 on tumor progression and metastasis using systemic Ang2 overexpression in mice carrying tumor xenografts, endothelium-specific overexpression of Ang2 in VEC-tTA/Tet-OS-Ang2 transgenic mice implanted with isogenic tumors, and administration of Ang2-blocking antibodies to tumor-bearing immunodeficient mice. Fisher's exact test was used for analysis of metastasis occurrence, and repeated measures one-way analysis of variance was used for the analysis of primary tumor growth curves. Unpaired t test was used for all other analyses. All statistical tests were two-sided.
Adenoviral expression of Ang2 increased lymph node and lung metastasis in tumor xenografts. The metastatic burden in the lungs was increased in transgenic mice in which Ang2 expression was induced specifically in the vascular endothelium (tumor burden per grid, VEC-tTA/Tet-OS-Ang2 mice [n = 5] vs control mice [n = 4]: 45.23 vs 12.26 mm(2), difference = 32.67 mm(2), 95% confidence interval = 31.87 to 34.07, P < .001). Ang2-blocking antibodies reduced lymph node and lung metastasis, as well as tumor lymphangiogenesis, and decreased tumor cell homing to the lungs after intravenous injection. In the lung metastases, Ang2 overexpression decreased endothelial integrity, whereas the Ang2-blocking antibodies improved endothelial cell-cell junctions and basement membrane contacts of metastasis-associated lung capillaries. At the cellular level, the Ang2-blocking antibodies induced the internalization of Ang2-Tie2 receptor complexes from endothelial cell-cell junctions in endothelial-tumor cell cocultures.
Our results indicate that blocking Ang2 inhibits metastatic dissemination in part by enhancing the integrity of endothelial cell-cell junctions.
血管生成素-2（Ang2）是内皮细胞 TEK（Tie2）酪氨酸激酶受体的配体，在肿瘤缺氧的内皮细胞中被诱导产生，促进肿瘤血管生成和生长。然而，Ang2 对肿瘤淋巴管生成和转移的影响尚未得到充分描述。
我们通过在携带肿瘤异种移植物的小鼠中系统性过表达 Ang2、在植入同源肿瘤的血管内皮细胞特异性过表达 Ang2 的 VEC-tTA/Tet-OS-Ang2 转基因小鼠中以及在荷瘤免疫缺陷小鼠中给予 Ang2 阻断抗体来研究 Ang2 对肿瘤进展和转移的影响。Fisher 确切检验用于分析转移的发生，重复测量单向方差分析用于分析原发性肿瘤生长曲线。所有其他分析均使用未配对 t 检验。所有统计检验均为双侧。
腺病毒表达的 Ang2 增加了肿瘤异种移植物中的淋巴结和肺转移。在血管内皮细胞特异性表达 Ang2 的转基因小鼠中（VEC-tTA/Tet-OS-Ang2 小鼠 [n = 5] 与对照小鼠 [n = 4]：肿瘤负荷每格 45.23 与 12.26 mm²，差异为 32.67 mm²，95%置信区间为 31.87 至 34.07，P <.001），肺转移的负担增加。Ang2 阻断抗体减少了淋巴结和肺转移以及肿瘤淋巴管生成，并减少了静脉注射后肿瘤细胞向肺部的归巢。在肺转移中，Ang2 过表达降低了内皮完整性，而 Ang2 阻断抗体改善了转移相关肺毛细血管内皮细胞-细胞连接和基底膜接触。在细胞水平上，Ang2 阻断抗体诱导内皮细胞-肿瘤细胞共培养中内皮细胞-细胞连接处的 Ang2-Tie2 受体复合物内化。
我们的结果表明，阻断 Ang2 通过增强内皮细胞-细胞连接的完整性抑制转移性播散。
Zotero 插件
