Angiopoietin-1 deficiency increases tumor metastasis in mice.

Michael IP; Orebrand M; Lima M; Pereira B; Volpert O; Quaggin SE; Jeansson M

doi:10.1186/s12885-017-3531-y

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Journal article

Angiopoietin-1 deficiency increases tumor metastasis in mice.

Michael IP Swiss Institute for Experimental Cancer Research, School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.
Orebrand M Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjoldsvagen 20, 751 85, Uppsala, Sweden.
Lima M Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Canada.
Pereira B Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjoldsvagen 20, 751 85, Uppsala, Sweden.
Volpert O Department of Urology, RH Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.
Quaggin SE Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, IL, USA.
Jeansson M Department of Immunology, Genetics and Pathology, Uppsala University, Dag Hammarskjoldsvagen 20, 751 85, Uppsala, Sweden. marie.jeansson@igp.uu.se.

2017-08-13

Published in:

BMC cancer. - 2017

Mammary Neoplasms, Experimental

English BACKGROUND
Angipoietin-1 activation of the tyrosine kinase receptor Tek expressed mainly on endothelial cells leads to survival and stabilization of endothelial cells. Studies have shown that Angiopoietin-1 counteracts permeability induced by a number of stimuli. Here, we test the hypothesis that loss of Angiopoietin-1/Tek signaling in the vasculature would increase metastasis.

METHODS
Angiopoietin-1 was deleted in mice just before birth using floxed Angiopoietin-1 and Tek mice crossed to doxycycline-inducible bitransgenic ROSA-rtTA/tetO-Cre mice. By crossing Angiopoietin-1 knockout mice to the MMTV-PyMT autochthonous mouse breast cancer model, we investigated primary tumor growth and metastasis to the lung. Furthermore, we utilized B16F10 melanoma cells subcutaneous and experimental lung metastasis models in Angiopoietin-1 and Tek knockout mice.

RESULTS
We found that primary tumor growth in MMTV-PyMT mice was unaffected, while metastasis to the lung was significantly increased in Angiopoietin-1 knockout MMTV-PyMT mice. In addition, angiopoietin-1 deficient mice exhibited a significant increase in lung metastasis of B16F10 melanoma cells, compared to wild type mice 3 weeks after injection. Additional experiments showed that this was likely an early event due to increased attachment or extravasation of tumor cells, since seeding of tumor cells was significantly increased 4 and 24 h post tail vein injection. Finally, using inducible Tek knockout mice, we showed a significant increase in tumor cell seeding to the lung, suggesting that Angiopoietin-1/Tek signaling is important for vascular integrity to limit metastasis.

CONCLUSIONS
This study show that loss of the Angiopoietin-1/Tek vascular growth factor system leads to increased metastasis without affecting primary tumor growth.

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