Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2-EphB4 Signaling in Melanoma Metastatic Spine Disease

TY - JOUR

T1 - Ligand-Dependent and Ligand-Independent Effects of Ephrin-B2-EphB4 Signaling in Melanoma Metastatic Spine Disease

AU - Piffko, Andras

AU - Broggini, Thomas

AU - Harms, Christoph

AU - Adams, Ralf Heinrich

AU - Vajkoczy, Peter

AU - Czabanka, Marcus

PY - 2021/7/27

Y1 - 2021/7/27

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Line, Tumor

KW - Ephrin-B2/genetics

KW - Ligands

KW - Melanoma, Experimental/drug therapy

KW - Mice

KW - Mice, Transgenic

KW - Neoplasm Metastasis

KW - Neoplasm Proteins/genetics

KW - Receptor, EphB4/genetics

KW - Signal Transduction

KW - Spinal Neoplasms/drug therapy

U2 - 10.3390/ijms22158028

DO - 10.3390/ijms22158028

M3 - SCORING: Journal article

C2 - 34360793

VL - 22

JO - INT J MOL SCI

JF - INT J MOL SCI

SN - 1661-6596

IS - 15

M1 - 8028

ER -