Abstract
BackgroundAngipoietin-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.MethodsAngiopoietin-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.ResultsWe 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.ConclusionsThis study show that loss of the Angiopoietin-1/Tek vascular growth factor system leads to increased metastasis without affecting primary tumor growth.
Highlights
Angipoietin-1 activation of the tyrosine kinase receptor Receptor tyrosine kinase (Tek) expressed mainly on endothelial cells leads to survival and stabilization of endothelial cells
To determine if Angpt1 plays a role in metastasis we used inducible whole body Angpt1 (Angpt1Δ/Δ) knockout mice crossed with the mammary tumor virus long terminal repeat (MMTV)-polyomavirus middle T (PyMT) transgenic mouse model of mammary tumors and lung metastasis
All MMTVPyMT positive mice developed mammary tumors, and the body weight was significantly increased in both MMTVPyMT- Angpt1Δ/Δ and MMTV-PyMT-weaning. Controls (WT) mice compared to MMTV-PyMT negative mice (Fig. 1a)
Summary
Angipoietin-1 activation of the tyrosine kinase receptor Tek expressed mainly on endothelial cells leads to survival and stabilization of endothelial cells. Angiopoietin-1 (Angpt1) is an activator of tyrosine kinase receptor Tek ( called Tie2) expressed mainly on endothelial cells. Tek activation and phosphorylation results in downstream signaling promoting vascular maturity and endothelial cell survival [2]. Angiopoietin-2 (Angpt2) antagonizes Angpt binding and Tek signaling in endothelial cells [3], but can act as a weak agonist in the absence of Angpt1 [4]. Angpt can activate integrins, leading to endothelial destabilization [7], an effect that may be increased in situations of low Tek expression [8]. In regards to vascular leakage, Angpt counteracts hyperpermeability induced by several leakage promoting stimuli [9, 10] while Angpt weakens the vascular barrier [11, 12]
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