Ligand-dependent and ligand-independent effects of Ephrin-B2-EphB4 signaling in melanoma metastatic spine disease

  • Tumor–endothelial cell interactions represent an essential mechanism in spinal metastasis. Ephrin-B2–EphB4 communication induces tumor cell repulsion from the endothelium in metastatic melanoma, reducing spinal bone metastasis formation. To shed further light on the Ephrin-B2–EphB4 signaling mechanism, we researched the effects of pharmacological EphB4 receptor stimulation and inhibition in a ligand-dependent/independent context. We chose a preventative and a post-diagnostic therapeutic window. EphB4 stimulation during tumor cell seeding led to an increase in spinal metastatic loci and number of disseminated melanoma cells, as well as earlier locomotion deficits in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, reduction of metastatic loci with a later manifestation of locomotion deficits occurred. Thus, EphB4 receptor stimulation affects metastatic dissemination depending on the presence/absence of endothelial Ephrin-B2. After the manifestation of solid metastasis, EphB4 kinase inhibition resulted in significantly earlier manifestation of locomotion deficits in the presence of the ligand. No post-diagnostic treatment effect was found in the absence of endothelial Ephrin-B2. For solid metastasis treatment, EphB4 kinase inhibition induced prometastatic effects in the presence of endothelial Ephrin-B2. In the absence of endothelial Ephrin-B2, both therapies showed no effect on the growth of solid metastasis.

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Author:András PiffkóORCiDGND, Thomas BrogginiORCiDGND, Christoph HarmsORCiD, Ralf Heinrich AdamsORCiD, Peter VajkoczyORCiDGND, Marcus Alexander CzabankaORCiDGND
Parent Title (English):International journal of molecular sciences
Publisher:Molecular Diversity Preservation International
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/07/27
Date of first Publication:2021/07/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2022/06/15
Tag:Ephrin-B2–EphB4; cancer therapy; seed and soil; spinal bone metastasis
Issue:15, art. 8028
Article Number:8028
Page Number:13
First Page:1
Last Page:13
This research was funded by the German research foundation DFG GEPRIS: 267716524 and the FOR2325 DFG Forschergruppe. A.P. received a Berlin Institute of Health (BIH) scholarship for this project. T.B. was a doctoral student of the Charité Medical Neuroscience, NeuroCure cluster of excellence graduate school, received the Ernst von Leyden fellowship from the ‘Berliner Krebsgesellschaft e.V.’ and the Early/Advanced Postdoc Mobility fellowship from the Swiss National Science Foundation. M.C. was part of the Friedrich C. Luft Clinical Scientist Pilot Program funded by the Volkswagen Foundation and the Charité Foundation.
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 53 Physik / 530 Physik
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0