Key result
Partial endothelial Rac1 deletion reduces tumor-induced vascular permeability and lung metastasis in mice.
Why the study?
Tumor-secreted vasoactive stimuli may induce endothelial permeability through Rac1, contributing to hematogenous metastasis, but this mechanism and its therapeutic potential were unclear.
Loss of Rac1 function in the endothelium attenuates tumor-induced vascular permeability and reduces hematogenous metastasis to the lungs in preclinical models.
Endothelial Rac1 may be a target to limit metastasis; hypothesis-generating in mice and leaves open human relevance.
// Hongyi Yao 1, 2, * , Wei Shi 2, * , Junsong Wu 3 , Chengyun Xu 2 , Jirong Wang 2 , Yanan Shao 2 , Ximei Wu 2 , Zhongmiao Zhang 1 1 Department of Pharmacy, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China 2 Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China 3 The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Ximei Wu, e-mail: xiwu@zju.edu.cn Zhongmiao Zhang, e-mail: zzmwhy@163.com Keywords: Rac1, vascular endothelial growth factor, permeability, metastasis Received: November 07, 2014 Accepted: April 28, 2015 Published: May 11, 2015 ABSTRACT 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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Yao et al. (2015) studied Hematogenous metastasis to the lung. Deletion of one copy of Rac1 in endothelium vs. Control was evaluated on Vascular permeability and metastasis of LLC to lungs. Deletion of one copy of Rac1 in the endothelium significantly attenuated tumor-induced vascular permeability and robustly reduced the metastasis of Lewis lung carcinoma cells to the lungs in mice.
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