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Endothelial Rac1 is essential for hematogenous metastasis to the lung
A variety of vasoactive stimuli induce endothelial permeability through Rac1, a membrane of Rho small GTPases. Here, we determine whether tumor-secreted vasoactive stimulant through Rac1 inducing permeability contributes to hematogenous metastasis. Activation of Rac1 was assayed in human umbilical v...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627324/ https://www.ncbi.nlm.nih.gov/pubmed/25991673 |
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author | Yao, Hongyi Shi, Wei Wu, Junsong Xu, Chengyun Wang, Jirong Shao, Yanan Wu, Ximei Zhang, Zhongmiao |
author_facet | Yao, Hongyi Shi, Wei Wu, Junsong Xu, Chengyun Wang, Jirong Shao, Yanan Wu, Ximei Zhang, Zhongmiao |
author_sort | Yao, Hongyi |
collection | PubMed |
description | A variety of vasoactive stimuli induce endothelial permeability through Rac1, a membrane of Rho small GTPases. Here, we determine whether tumor-secreted vasoactive stimulant through Rac1 inducing permeability contributes to hematogenous metastasis. Activation of Rac1 was assayed in human umbilical vein endothelial cells (HUVEC), transendothelial passages were measured by Transwell chambers, and hematogenously metastatic mouse model was generated by intravenous injection with Lewis lung carcinoma cells (LLC). LLC secreted abundant vascular endothelial growth factor (VEGF) in the culture media and sera of mice bearing LLC xenografts or metastatic LLC, and VEGF activated Rac1 through VEGF receptors/PI3Kβ signaling cascade, resulting in hyperoxidative stress and consequent hyperpermeability in HUVEC. Moreover, in co-culture of LLC and HUVEC, significant increases in endothelial permeability and transendothelial migration of LLC were robustly attenuated by either anti-VEGF neutralizing antibody or Rac1 knockdown in HUVEC. Finally, in metastatic mouse model, deletion of one copy of Rac1 in endothelium not only significantly attenuated LLC-induced vascular permeability, but robustly reduced the metastasis of LLC to lungs. This study supports that tumor-secreted vasoactive stimuli activate Rac1 to induce permeability and consequent transendothelial migration of tumor cells, and that loss of Rac1 function in endothelium is an effective therapeutic intervention for hematogenous metastasis. |
format | Online Article Text |
id | pubmed-4627324 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-46273242015-12-02 Endothelial Rac1 is essential for hematogenous metastasis to the lung Yao, Hongyi Shi, Wei Wu, Junsong Xu, Chengyun Wang, Jirong Shao, Yanan Wu, Ximei Zhang, Zhongmiao Oncotarget Research Paper A variety of vasoactive stimuli induce endothelial permeability through Rac1, a membrane of Rho small GTPases. Here, we determine whether tumor-secreted vasoactive stimulant through Rac1 inducing permeability contributes to hematogenous metastasis. Activation of Rac1 was assayed in human umbilical vein endothelial cells (HUVEC), transendothelial passages were measured by Transwell chambers, and hematogenously metastatic mouse model was generated by intravenous injection with Lewis lung carcinoma cells (LLC). LLC secreted abundant vascular endothelial growth factor (VEGF) in the culture media and sera of mice bearing LLC xenografts or metastatic LLC, and VEGF activated Rac1 through VEGF receptors/PI3Kβ signaling cascade, resulting in hyperoxidative stress and consequent hyperpermeability in HUVEC. Moreover, in co-culture of LLC and HUVEC, significant increases in endothelial permeability and transendothelial migration of LLC were robustly attenuated by either anti-VEGF neutralizing antibody or Rac1 knockdown in HUVEC. Finally, in metastatic mouse model, deletion of one copy of Rac1 in endothelium not only significantly attenuated LLC-induced vascular permeability, but robustly reduced the metastasis of LLC to lungs. This study supports that tumor-secreted vasoactive stimuli activate Rac1 to induce permeability and consequent transendothelial migration of tumor cells, and that loss of Rac1 function in endothelium is an effective therapeutic intervention for hematogenous metastasis. Impact Journals LLC 2015-05-11 /pmc/articles/PMC4627324/ /pubmed/25991673 Text en Copyright: © 2015 Yao et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Yao, Hongyi Shi, Wei Wu, Junsong Xu, Chengyun Wang, Jirong Shao, Yanan Wu, Ximei Zhang, Zhongmiao Endothelial Rac1 is essential for hematogenous metastasis to the lung |
title | Endothelial Rac1 is essential for hematogenous metastasis to the lung |
title_full | Endothelial Rac1 is essential for hematogenous metastasis to the lung |
title_fullStr | Endothelial Rac1 is essential for hematogenous metastasis to the lung |
title_full_unstemmed | Endothelial Rac1 is essential for hematogenous metastasis to the lung |
title_short | Endothelial Rac1 is essential for hematogenous metastasis to the lung |
title_sort | endothelial rac1 is essential for hematogenous metastasis to the lung |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627324/ https://www.ncbi.nlm.nih.gov/pubmed/25991673 |
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