Slit2N and Robo4 regulate lymphangiogenesis through the VEGF-C/VEGFR-3 pathway

Cell Communication and Signaling

Research

Weiquan Zhu¹  Dean Y Li²  Xuefeng Zhang³  Paula M Kuzontkoski³  Jerome E Groopman³  Shuxian Jiang³  Jinlong Yu⁴ 

[1] Department of Molecular Medicine and Molecular Medicine Program, University of Utah, 84112, Salt Lake City, UT, USA;Department of Molecular Medicine and Molecular Medicine Program, University of Utah, 84112, Salt Lake City, UT, USA;The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, 610072, Chengdu, Sichuan, China;Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, 02115, Boston, MA, USA;Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, 02115, Boston, MA, USA;Division of Hematology/Oncology, Department of Medicine, University of Florida, 32610, Gainesville, FL, USA;

关键词: Slit2;    Robo4;    VEGF-C;    VEGFR-3;    Akt;    PI3K;    Proliferation;    Migration;    Lymphangiogenesis;   

DOI  :  10.1186/1478-811X-12-25

 received in 2013-07-17, accepted in 2014-02-21,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundSignaling through vascular endothelial growth factor C (VEGF–C) and VEGF receptor 3 (VEGFR-3) plays a central role in lymphangiogenesis and the metastasis of several cancers via the lymphatics. Recently, the Slit2/Robo4 pathway has been recognized as a modulator of vascular permeability and integrity. Signaling via the Robo receptor inhibits VEGF-mediated effects; however, its effects on lymphatic endothelial cell function have not been well characterized.ResultsWe found that pretreatment with Slit2N, an active fragment of Slit2, inhibited VEGF-C-mediated lung-derived lymphatic endothelial cell (L-LEC) proliferation, migration, and in vitro tube formation. Slit2N induced the internalization of VEGFR-3, which blocked its activation, and inhibited the activation of the PI3K/Akt pathway by VEGF-C in L-LECs. Moreover, we found that inhibition of VEGF-C-induced effects by Slit2N was Robo4-dependent.ConclusionThese results indicate that Slit2N/Robo4 modulates several key cellular functions, which contribute to lymphangiogenesis, and identify this ligand-receptor pair as a potential therapeutic target to inhibit lymphatic metastasis of VEGF-C-overexpressing cancers and manage lymphatic dysfunctions characterized by VEGF-C/VEGFR-3 activation.

【 授权许可】

Unknown   
© Yu et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.