Article
Endothelial EphrinB2 mediates spinal metastasis formation
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Published: | May 13, 2014 |
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Objective: Current understanding of metastasis formation postulates a multi-step process involving tumor cell intravasation, intravascular circulation, extravasation and intraparenchymal metastasis growth/dormancy. The molecular principles of metastasis formation in the spine remain unknown. The EphrinB2 system has been linked to organ-specific metastasis formation by mediating tumor cell-endothelial cell interactions facilitating tumor cell extravasation. It was the aim to investigate the role of the EphrinB2 system for spinal metastasis formation in vivo.
Method: Luciferin-transfected B16 melanoma cells (5*105 cells) were injected retrograde into the left common carotid artery in control and endothelial EphrinB2 Knock-out mice (N=5). Bioluminescence analysis, spinal MRI and organ-specific luciferin analysis were performed to analyse following parameters: time to neurological deficit, number of spinal metastasis, average metastasis volume, tumor volume, number of metastatic cells per organ. Organs were resected for luciferin-analysis mediated characterization of non spinal metastasis distribution.
Results: Time to neurological deficit was significantly reduced in EphrinB2-KO compared to control animals (24±1days vs. 28±1days). Number of spinal metastasis and tumor volume was significantly increased in EphrinB2-KO (1,2±0,4 vs. 3,8±1,7; 18±6mm3 vs. 51±10mm3). Average metastasis volume was unchanged in EphrinB2 KO (2,2±1,2mm3 vs. 2,8±1,6mm3). EphrinB2-KO induced increased metastasis formation in osseous organs compared to non-osseous organs (Bone: 10,4x107 ±2,2 x107 cells vs Other: 5,1±1,4 x107 cells).
Conclusions: Endothelial EphrinB2 depletion mediates metastasis formation to the spine and may predispose to increased metastasis formation in osseous organs. This may facilitate the development of targeted therapies for spinal metastasis.