Artikel
EphrinB2 - EphB4 pathway as a therapeutic target in spinal metastasis formation
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Autoren
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Andras Piffko
- Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Germany
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Thomas Broggini
- Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Germany
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Peter Vajkoczy
- Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Germany
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Marcus Czabanka
- Department of Neurosurgery, Charité - Universitätsmedizin Berlin, Germany
| Veröffentlicht: | 8. Juni 2016 |
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Gliederung
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Objective: Clinical treatment of spinal metastases represents a complex problem of not only oncological but also of surgical nature. In osseous metastases, the extravasation process of the circulating tumour cells is facilitated by adhesion molecules of the Eph-receptor family. EphrinB2-EphB4 interaction also affects tumour angiogenesis by facilitating cellular internalisation of the VEGF receptor 2. The aim of the study is to examine the effect of the EphrinB2- EphB4 system on spinal metastasis formation and to evaluate a potential for therapeutic alteration by molecular inhibition of the EphrinB2-EphB4 interaction.
Method: 100.000 luciferase-expressing bioluminescent melanoma tumour cells were injected retrogradely into the carotid artery of EphrinB2-knockout (efnb2iΔEC) and control mice. The antibody fragment EphrinB2-Fc as well as NVP BHG712, a small molecular inhibitor of the EphB4-receptor kinase were applied 15 days after tumor cell injection. Tumor growth and dissemination were visualized in vivo by bioluminescent imaging procedures, epidural myelon compression was identified using repetitive MRI imaging. The appearance of a neurological phenotype was evaluated daily.
Results: Ephrin B2-knockout mice that were treated with EphrinB2-Fc showed a significantly prolonged walking ability compared to mice that received placebo treatment. (23 vs. 18 days, n = 6). Furthermore the inhibition of the EphB4 kinase by applying NVP BHG712 was also able to significantly alter the appearance of spinal metastases. (21 vs. 18.5 days, n = 6). In control mice, no significant difference between the appearances of a paraplegic phenotype in placebo or treatment groups could be observed.
Conclusions: Altering the molecular interaction between EphB4 and Ephrin B2 significantly delays the appearance of a neurological phenotype maintaining walking ability in Ephrin B2 (efnb2iΔEC) knockout mice. This effect is not observed in control animals underlining the importance of complete inhibition of the EphrinB2-EphB4 pathway in order to induce therapeutic effects on spinal metastasis.
