Apelin promotes lymphangiogenesis and lymph node metastasis
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Judit Berta1,2,*, Mir Alireza Hoda1,*, Viktoria Laszlo1,3, Anita Rozsas1,2, Tamas Garay2,3,4, Szilvia Torok2, Michael Grusch5, Walter Berger5, Sandor Paku3,6, Ferenc Renyi-Vamos1,7, Bernard Masri8, Jozsef Tovari9, Marion Groger10,11, Walter Klepetko1, Balazs Hegedus1,4, Balazs Dome1,2,7
1 Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria
2 Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary
3 Department of Biological Physics, Eötvös Loránd University, Budapest, Hungary
4 MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary
5 Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Austria
6 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
7 Thoracic Surgery, National Institute of Oncology and Semmelweis University, Budapest, Hungary
8 Cancer Research Center of Toulouse, INSERM U1037-Université Paul Sabatier Toulouse III, Toulouse, France
9 Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary; Skin and Endothelium Research Division (SERD)
10 Department of Dermatology, Medical University of Vienna, Austria
11 Core Facility Imaging, Core Facilities, Medical University of Vienna, Austria
* These authors contributed equally to this work
** These authors share last authorship
Balazs Dome, email:
Keywords: apelin, APJ, lymphangiogenesis, lymph node metastasis
Received: April 8, 2014 Accepted: May 27, 2014 Published: May 28, 2014
Whereas the role of the G-protein-coupled APJ receptor and its ligand, apelin, in angiogenesis has been well documented, the ability of the apelin/APJ system to induce lymphangiogenesis and lymphatic metastasis has been largely unexplored. To this end, we first show that APJ is expressed in lymphatic endothelial cells (LECs) and, moreover, that it responds to apelin by activating the apelinergic signaling cascade. We find that although apelin treatment does not influence the proliferation of LECs in vitro, it enhances their migration, protects them against UV irradiation-induced apoptosis, increases their spheroid numbers in 3D culture, stimulates their in vitro capillary-like tube formation and, furthermore, promotes the invasive growth of lymphatic microvessels in vivo in the matrigel plug assay. We also demonstrate that apelin overexpression in malignant cells is associated with accelerated in vivo tumor growth and with increased intratumoral lymphangiogenesis and lymph node metastasis. These results indicate that apelin induces lymphangiogenesis and, accordingly, plays an important role in lymphatic tumor progression. Our study does not only reveal apelin as a novel lymphangiogenic factor but might also open the door for the development of novel anticancer therapies targeting lymphangiogenesis.
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