Influence of the EphrinB2-EphB4 system on spinal metastasis formation
Clinical Neurology; Neurosurgery and Neuroradiology
Final Report Abstract
Spinal metastasis is an emerging clinical phenomenon as a result of primary tumor therapy improvements. For patient’s, spinal metastasis involves a significant clinical burden including abrupt spinal cord compression, loss of motor capabilities, sensory disfunction, pain, thoracal instability, and other severe reductions in quality of live. As clinicians our arsenal to combat this devastating disease is limited. Manly caused by our lack of molecular knowledge about the disease. We set out to characterize the ephrinB2 – EphB4 cell-cell interaction pathway as a potential therapeutic target. Endothelial ephrinB2 was described as proangiogenic and the interaction with EphB4 expressed in tumor cells can be promoting or demoting depending on the tumor type and environment. It was unknown how interventions would play out. We expected an antiangiogenic effect and a tumor cell – endothelial cell interaction effect. We identified the ephrinB2-EphB4 interaction is most important during tumor cell seeding in the initial phase of metastasis. We performed different therapeutic interventions with and without ephrinB2 expression in endothelial cells. In the seeding phase of the metastasis blocking the pathway was metastasis promoting and resulted in faster spinal cord compressions and multiple metastatic loci. Interventions in the growth phase of the tumors after seeding to the spine, surprisingly had very little effect on the clinical outcome in mice. Even though, we found increased apoptosis when blocking the EphB4 tyrosine kinase. This did not manifest in a better clinical performance in this group. Early interventions in people are currently impossible in people, the detection of circulating tumor cells is possible, given a stringent diagnostic protocol that could identify the first event to initiate therapy in time. This must activate the ephrinB2 – EphB4 pathway, a therapy not developed to date. Concluding, we identified a new target involved in metastatic seeding, with therapeutic potential when activated and initiated in the early phase of metastasis.
Publications
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Broggini T, Czabanka M, Piffko A, Harms C, Hoffmann C, Mrowka R, Wenke F, Deutsch U, Grötzinger C, Vajkoczy P
(See online at https://doi.org/10.1007/s00586-015-3811-7) - Passive Entrapment of Tumor Cells Determines Metastatic Dissemination to Spinal Bone and Other Osseous Tissues. PLoS One. 2016 Sep 7;11(9):e0162540
Broggini T, Piffko A, Hoffmann CJ, Harms C, Vajkoczy P, Czabanka M
(See online at https://doi.org/10.1371/journal.pone.0162540) - Ephrin-B2-EphB4 communication mediates tumor-endothelial cell interactions during hematogenous spread to spinal bone in a melanoma metastasis model. Oncogene. 2020 Nov;39(47):7063-7075
Broggini T, Piffko A, Hoffmann CJ, Ghori A, Harms C, Adams RH, Vajkoczy P, Czabanka M
(See online at https://doi.org/10.1038/s41388-020-01473-y) - Role of mTOR and VEGFR Inhibition in Prevention of Metastatic Tumor Growth in the Spine. Front Oncol. 2020 Feb 19;10:174
Kratzsch T, Piffko A, Broggini T, Czabanka M, Vajkoczy P
(See online at https://doi.org/10.3389/fonc.2020.00174) - Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2-EphB4 Signaling in Melanoma Metastatic Spine Disease. Int J Mol Sci. 2021 Jul 27;22(15):8028
Piffko A, Broggini T, Harms C, Adams RH, Vajkoczy P, Czabanka M
(See online at https://doi.org/10.3390/ijms22158028)
