Angiopoietin-1 deficiency increases tumor metastasis in mice.
Angiopoietin-1 deficiency increases tumor metastasis in mice.
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DOI：
10.1186/s12885-017-3531-y
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发表时间：
2017-08-11
期刊：
影响因子：
3.8
通讯作者：
Jeansson M
中科院分区：
文献类型：
--
作者：
Michael IP;Orebrand M;Lima M;Pereira B;Volpert O;Quaggin SE;Jeansson M
主要在内皮细胞上表达的酪氨酸激酶受体Tek的血管生成素-1活化导致内皮细胞的存活和稳定。研究表明，血管生成素-1抵消渗透性诱导的一些刺激。在这里，我们测试的假设，血管生成素-1/Tek信号的损失将增加转移。使用floxed Angiopoietin-1和Tek小鼠与多西环素诱导的双转基因ROSA-rtTA/tetO-Cre小鼠杂交，在出生前删除小鼠中的Angiopoietin-1。通过将Angiopoietin-1敲除小鼠与MMTV-PyMT自体小鼠乳腺癌模型杂交，我们研究了原发性肿瘤生长和肺转移。此外，我们在Angiopoietin-1和Tek敲除小鼠中利用B16 F10黑色素瘤细胞皮下和实验肺转移模型。我们发现MMTV-PyMT小鼠的原发性肿瘤生长不受影响，而Angiopoietin-1敲除MMTV-PyMT小鼠的肺转移显着增加。此外，与注射后3周的野生型小鼠相比，血管生成素-1缺陷型小鼠表现出B16 F10黑素瘤细胞肺转移的显著增加。其他实验表明，这可能是由于肿瘤细胞附着或外渗增加所致的早期事件，因为肿瘤细胞的接种在尾静脉注射后4和24小时显著增加。最后，使用可诱导的Tek基因敲除小鼠，我们显示了肿瘤细胞向肺的接种显著增加，这表明血管生成素-1/Tek信号传导对于血管完整性限制转移是重要的。这项研究表明，血管生成素-1/Tek血管生长因子系统的丢失导致转移增加，而不影响原发性肿瘤生长。
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. 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. 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. 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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影响因子：
8.8
作者：
Peeters, M.;Strickland, A. H.;Lichinitser, M.;Suresh, A. V. S.;Manikhas, G.;Shapiro, J.;Rogowski, W.;Huang, X.;Wu, B.;Warner, D.;Jain, R.;Tebbutt, N. C.
通讯作者：
Tebbutt, N. C.
影响因子：
15.8
作者：
Parikh SM;Mammoto T;Schultz A;Yuan HT;Christiani D;Karumanchi SA;Sukhatme VP
通讯作者：
Sukhatme VP
影响因子：
11.8
作者：
Gale, NW;Thurston, G;Yancopoulos, GD
通讯作者：
Yancopoulos, GD
影响因子：
51.1
作者：
Monk, Bradley J.;Poveda, Andres;Oza, Amit M.
通讯作者：
Oza, Amit M.
影响因子：
50.5
作者：
Eatock, M. M.;Tebbutt, N. C.;Bodoky, G.
通讯作者：
Bodoky, G.