Effects of Angiopoietin-2-Blocking Antibody on Endothelial Cell–Cell Junctions and Lung Metastasis
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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.
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Antibodies blocking the Ang2-Tie2 interaction reduce tumour cell transendothelial migration.
“We found that antibodies blocking the Ang2–Tie2 interaction reduced tumour cell transendothelial migration, in line with previously published in vivo data19.”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [19]
The Discussion reports fewer early lung tumour-cell colonies after Ang2-blocking antibody treatment and suggests that blocking Ang2 may inhibit extravasation. It also states that extravasation was not imaged, so the paper provides consistent in vivo evidence rather than a direct finding of reduced transendothelial migration. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTransgenic overexpression of ANGPT2 in mice leads to aberrant and decreased EC-basement membrane matrix interactions.
“transgenic overexpression of ANGPT2 in mice leads to aberrant and decreased EC-basement membrane matrix interactions (27, 28).”
From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [28]
In lung metastases, Ang2 inhibition improved capillary integrity, while transgenic endothelial Ang2 expression decreased capillary integrity, indicating that blocking Ang2 inhibits metastatic dissemination in part by enhancing the integrity of endothelial cell-cell junctions.
“In lung metastases, Ang2 inhibition improved, while transgenic endothelial Ang2 expression decreased capillary integrity, indicating that blocking Ang2 inhibits metastatic dissemination, in part, by enhancing the integrity of endothelial cell–cell junctions19”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [19]
These changes were much less prominent in wild-type tumour-bearing littermates, suggesting that increased Ang2 levels aggravated endothelial destabilization induced by tumour cells in the lungs.
“These changes were much less prominent in wild-type (WT) tumour-bearing littermates19, suggesting that increased Ang2 levels aggravated endothelial destablization induced by the tumour cells in the lungs.”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [19]
The VEC-tTA/Tet-OS-Ang2 mouse line expresses mouse Ang2 under an inducible endothelial cell promoter.
“We used the VEC-tTA/Tet-OS-Ang2 mouse line, which expresses mouse Ang2 under an inducible endothelial cell promoter19.”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [19]
Endothelial Ang2 overexpression causes embryonic lethality in double-transgenic embryos.
“To overcome the embryonic lethality due to endothelial Ang2 overexpression in double-transgenic embryos, Ang2 expression was repressed during the entire pregnancy.”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [19]
Induced expression of murine Ang2 in the endothelium of double-transgenic mice (VEC-tTA/Ang2) results in increased lung metastasis and marked capillary changes in vessels adjacent to extravasated tumour cells, including endothelial cell-basement membrane detachment, reduced endothelial cell-cell junctions and gaps between endothelial cells.
“In our previous studies, induced expression of murine Ang2 in the endothelium of double-transgenic mice (VE-cadherin-tTA (VEC-tTA)/Tet-OS-Ang2 mice; VEC-tTA/Ang2 for short) resulted in increased lung metastasis, and marked capillary changes in vessels adjacent to extravasated tumour cells, including endothelial cell-basement membrane detachment, reduced endothelial cell–cell junctions and gaps”
From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [19]
Transgenic mice with endothelial cell-specific overexpression of ANG2 have decreased endothelial integrity, resulting in increased metastatic foci formation in the Lewis lung carcinoma model.
“transgenic mice with EC-specific overexpression of ANG2 have decreased endothelial integrity, resulting in increased metastatic foci formation in the Lewis lung carcinoma model32”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [32]
ANG2 disrupts endothelial cell-pericyte contacts, facilitating migration of immune cells out of the vasculature and into the tumour microenvironment.
“Second, ANG2 disrupts EC–pericyte contacts, thus facilitating the migration of immune cells out of the vasculature and into the TME32,33”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [32]
Metastatic dissemination could be prevented by treatment with an ANG2-neutralizing antibody in mice.
“metastatic dissemination could be prevented by treatment of the mice with an ANG2-neutralizing antibody32”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [32]
Dual VEGF-ANG2 blockade can provide tumour control in some preclinical models, but the degree of benefit and mechanism appear context-dependent.
“This dual blockade approach can provide tumour control in some preclinical models, although the degree of benefit and the underlying mechanism of action seem to be context-dependent31,32,80,89.”
From Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges (2018) · cites this paper as [32]
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“In line with this conclusion, transgenic overexpression of ANGPT2 in mice leads to aberrant and decreased EC-basement membrane matrix interactions (27, 28).”
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Characterization of <i>ANGPT2</i> mutations associated with primary lymphedema
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Self-citationAngiopoietin–TIE2 feedforward circuit promotes PIK3CA-driven venous malformations
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Endothelial Pim3 kinase protects the vascular barrier during lung metastasis
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Self-citation
- Authors
- Holopainen, T., Saharinen, P., D’Amico, G., Lampinen, A., Eklund, L., Sormunen, R., Anisimov, A., Zarkada, G., Lohela, M., Heloterä, H., Tammela, T., Benjamin, L. E., Ylä-Herttuala, S., Leow, C. C., Koh, G. Y., & Alitalo, K.
- Affiliations
- University of Helsinki (FI)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Alitalo, Kari
- ORCID
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-02-17
- Volume
- 104
- Issue
- 6
- Pages
- 461-475
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- PMC
- PMC3309130
- OpenAlex
- W1571910417
- Cited by
- 216
- References
- 49
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 16 · 2023: 8 · 2022: 10 · 2021: 15 · 2020: 14 · 2019: 18 · 2018: 11 · 2017: 18 · 2016: 21 · 2015: 15 · 2014: 25 · 2013: 23 · 2012: 12
- FWCI
- 9.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Oncology › Vascular Tumors and Angiosarcomas
- Keywords
- angiopoietin-2, Tie2 receptor, lung metastasis, lymph node metastasis, tumor lymphangiogenesis, endothelial junctions, endothelial integrity, tumor cell homing, tumor xenografts, receptor internalization
- MeSH terms
- Animals, Endothelium, Vascular, Female, Immunohistochemistry, Intercellular Junctions, Lung Neoplasms, Lymphatic Metastasis, Melanoma, Mice, Inbred BALB C, Mice, Transgenic, Neovascularization, Pathologic, Retinal Vessels, Transplantation, Heterologous, Immunoblotting, Cell Hypoxia, Up-Regulation, Mice, SCID, Coculture Techniques, Antibodies, Blocking, Angiogenesis Inhibitors, Lymphangiogenesis, Angiopoietin-2, Endothelial Cells, Receptor, TIE-2, Microscopy, Electron, Transmission, Immunoprecipitation, Mice
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