EphB4 Promotes Site-Specific Metastatic Tumor Cell Dissemination by Interacting with Endothelial Cell-Expressed EphrinB2

被引:42
作者
Heroult, Melanie [2 ]
Schaffner, Florence [4 ]
Pfaff, Dennis [2 ]
Prahst, Claudia [2 ]
Kirmse, Robert [3 ]
Kutschera, Simone [2 ]
Riedel, Maria
Ludwig, Thomas [3 ]
Vajkoczy, Peter [6 ]
Graeser, Ralph [5 ]
Augustin, Hellmut G. [1 ,2 ]
机构
[1] Univ Heidelberg, Joint Res Div Vasc Biol, Med Fac Mannheim CBTM, D-69120 Heidelberg, Germany
[2] German Canc Res Ctr Heidelberg DKFZ ZMBH Alliance, Heidelberg, Germany
[3] German Canc Res Ctr Heidelberg DKFZ, Dept Microenvironm Tumor Cell Invas, BioQuant Zentrum, Heidelberg, Germany
[4] Tumor Biol Ctr, Dept Vasc Biol & Angiogenesis Res, Freiburg, Germany
[5] ProQinase GmbH, Freiburg, Germany
[6] Charite, Dept Neurosurg, D-13353 Berlin, Germany
关键词
RECEPTOR-TYROSINE KINASE; BREAST-CANCER METASTASIS; LUNG METASTASIS; ADHESION MOLECULE; MIGRATION; GROWTH; CARCINOMA; MORPHOGENESIS; ANGIOGENESIS; INHIBITION;
D O I
10.1158/1541-7786.MCR-09-0453
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The tyrosine kinase receptor EphB4 interacts with its ephrinB2 ligand to act as a bidirectional signaling system that mediates adhesion, migration, and guidance by controlling attractive and repulsive activities. Recent findings have shown that hematopoietic cells expressing EphB4 exert adhesive functions towards endothelial cells expressing ephrinB2. We therefore hypothesized that EphB4/ephrinB2 interactions may be involved in the preferential adhesion of EphB4-expressing tumor cells to ephrinB2-expressing endothelial cells. Screening of a panel of human tumor cell lines identified EphB4 expression in nearly all analyzed tumor cell lines. Human A375 melanoma cells engineered to express either full-length EphB4 or truncated EphB4 variants which lack the cytoplasmic catalytic domain (Delta C-EphB4) adhered preferentially to ephrinB2-expressing endothelial cells. Force spectroscopy by atomic force microscopy confirmed, on the single cell level, the rapid and direct adhesive interaction between EphB4 and ephrinB2. Tumor cell trafficking experiments in vivo using sensitive luciferase detection techniques revealed significantly more EphB4-expressing A375 cells but not Delta C-EphB4-expressing or mock-transduced control cells in the lungs, the liver, and the kidneys. Correspondingly, ephrinB2 expression was detected in the microvessels of these organs. The specificity of the EphB4-mediated tumor homing phenotype was validated by blocking the EphB4/ephrinB2 interaction with soluble EphB4-Fc. Taken together, these experiments identify adhesive EphB4/ephrinB2 interactions between tumor cells and endothelial cells as a mechanism for the site-specific metastatic dissemination of tumor cells. Mol Cancer Res; 8(10); 1297-309. (C) 2010 AACR.
引用
收藏
页码:1297 / 1309
页数:13
相关论文
共 53 条
[1]   Molecular regulation of angiogenesis and lymphangiogenesis [J].
Adams, Ralf H. ;
Alitalo, Kari .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (06) :464-478
[2]   The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration [J].
Adams, RH ;
Diella, F ;
Hennig, S ;
Helmbacher, F ;
Deutsch, U ;
Klein, R .
CELL, 2001, 104 (01) :57-69
[3]   Models, mechanisms and clinical evidence for cancer dormancy [J].
Aguirre-Ghiso, Julio A. .
NATURE REVIEWS CANCER, 2007, 7 (11) :834-846
[4]   EphB receptor activity suppresses colorectal cancer progression [J].
Batlle, E ;
Bacani, J ;
Begthel, H ;
Jonkeer, S ;
Gregorieff, A ;
van de Born, M ;
Malats, N ;
Sancho, E ;
Boon, E ;
Pawson, T ;
Gallinger, S ;
Pals, S ;
Clevers, H .
NATURE, 2005, 435 (7045) :1126-1130
[5]   Metadherin, a cell surface protein in breast tumors that mediates lung metastasis [J].
Brown, DM ;
Ruoslahti, E .
CANCER CELL, 2004, 5 (04) :365-374
[6]   HOST AND TUMOR FACTORS IN CANCER METASTASIS [J].
FIDLER, IJ .
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 1990, 20 (05) :481-486
[7]   Timeline - The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited [J].
Fidler, IJ .
NATURE REVIEWS CANCER, 2003, 3 (06) :453-458
[8]   METASTASIS RESULTS FROM PREEXISTING VARIANT CELLS WITHIN A MALIGNANT-TUMOR [J].
FIDLER, IJ ;
KRIPKE, ML .
SCIENCE, 1977, 197 (4306) :893-895
[9]  
Franz C.M., 2007, SCI STKE, V2007, P15
[10]   Forward EphB4 signaling in endothelial cells controls cellular repulsion and segregation from ephrinB2 positive cells [J].
Füller, T ;
Korff, T ;
Kilian, A ;
Dandekar, G ;
Augustin, HG .
JOURNAL OF CELL SCIENCE, 2003, 116 (12) :2461-2470