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Angiopoietin-1 deficiency increases tumor metastasis in mice
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- Iacovos, Michael (author)
- Swiss Fed Inst Technol Lausanne EPFL, Swiss Inst Expt Canc Res, Sch Life Sci, Lausanne, Switzerland
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- Orebrand, Martina (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Lima, Marta (author)
- Univ Toronto, Matrix Dynam Grp, Fac Dent, Toronto, ON, Canada
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- 2017-08-11
- 2017
- English.
- In: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 17
- Journal article (peer-reviewed)
Abstract
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- 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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- Medicinsk vetenskap
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- Quaggin, Susan
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