Effects of Angiopoietin-2-Blocking Antibody on Endothelial Cell-Cell Junctions and Lung Metastasis

被引:173
作者
Holopainen, Tanja [4 ,5 ]
Saharinen, Pipsa
D'Amico, Gabriela [4 ,5 ]
Lampinen, Anita
Eklund, Lauri [6 ]
Sormunen, Raija [7 ]
Anisimov, Andrey [4 ,5 ]
Zarkada, Georgia [4 ,5 ]
Lohela, Marja [2 ]
Helotera, Hanna [4 ,5 ]
Tammela, Tuomas [3 ,4 ,5 ]
Benjamin, Laura E. [8 ]
Yla-Herttuala, Seppo [9 ]
Leow, Ching Ching [10 ]
Koh, Gou Young [11 ,12 ]
Alitalo, Kari [1 ]
机构
[1] Univ Helsinki, Mol Canc Biol Lab, Biomedicum Helsinki, Mol Canc Biol Program,Res Programs Unit, FI-00014 Helsinki, Finland
[2] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA
[3] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA
[4] Inst Mol Med Finland, Helsinki, Finland
[5] Univ Helsinki, Helsinki Univ Cent Hosp, FI-00014 Helsinki, Finland
[6] Univ Oulu, Dept Med Biochem & Mol Biol, Oulu Ctr Cell Matrix Res, Bioctr Oulu, Oulu, Finland
[7] Univ Oulu, Dept Pathol, Bioctr Oulu, Oulu, Finland
[8] Harvard Univ, Beth Israel Deaconess Med Ctr, Dept Pathol, Sch Med, Boston, MA 02215 USA
[9] Univ Eastern Finland, Dept Mol Med, AI Virtanen Inst, Kuopio, Finland
[10] MedImmune, Dept Preclin Oncol, Gaithersburg, MD USA
[11] Korea Adv Inst Sci & Technol, Biomed Res Ctr, Taejon 305701, South Korea
[12] Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea
基金
芬兰科学院;
关键词
RECEPTOR TYROSINE KINASE; TUMOR-GROWTH; IN-VIVO; TRANSGENE EXPRESSION; LYMPHATIC VESSELS; TIE2; RECEPTOR; GENE-THERAPY; VEGF-C; ANGIOGENESIS; CANCER;
D O I
10.1093/jnci/djs009
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background 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. Methods 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. Results 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. Conclusion Our results indicate that blocking Ang2 inhibits metastatic dissemination in part by enhancing the integrity of endothelial cell cell junctions.
引用
收藏
页码:461 / 475
页数:15
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