Endothelial Rac1 is essential for hematogenous metastasis to the lung
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Hongyi Yao1,2,*, Wei Shi2,*, Junsong Wu3, Chengyun Xu2, Jirong Wang2, Yanan Shao2, Ximei Wu2, Zhongmiao Zhang1
1Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
2Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China
3The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
*These authors have contributed equally to this work
Ximei Wu, e-mail: [email protected]
Zhongmiao Zhang, e-mail: [email protected]
Keywords: Rac1, vascular endothelial growth factor, permeability, metastasis
Received: November 07, 2014 Accepted: April 28, 2015 Published: May 11, 2015
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.
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