Ephrin-B2-EphB4 communication mediates tumor-endothelial cell interactions during hematogenous spread to spinal bone in a melanoma metastasis model.
Animals
Bone Marrow
/ diagnostic imaging
Cell Adhesion
Cell Communication
/ drug effects
Cell Line, Tumor
/ transplantation
Endothelial Cells
/ pathology
Female
Intravital Microscopy
Magnetic Resonance Imaging
Male
Melanoma, Experimental
/ drug therapy
Mice
Mice, Knockout
Microscopy, Video
Osteoblasts
/ pathology
Pyrazoles
/ pharmacology
Pyrimidines
/ pharmacology
Receptor, EphB2
/ genetics
Receptor, EphB4
/ antagonists & inhibitors
Skin Neoplasms
/ drug therapy
Skull
/ pathology
Spinal Cord Compression
/ diagnosis
Spinal Neoplasms
/ complications
Spine
/ cytology
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
16
12
2019
accepted:
15
09
2020
revised:
21
08
2020
pubmed:
30
9
2020
medline:
15
12
2020
entrez:
29
9
2020
Statut:
ppublish
Résumé
Metastases account for the majority of cancer deaths. Bone represents one of the most common sites of distant metastases, and spinal bone metastasis is the most common source of neurological morbidity in cancer patients. During metastatic seeding of cancer cells, endothelial-tumor cell interactions govern extravasation to the bone and potentially represent one of the first points of action for antimetastatic treatment. The ephrin-B2-EphB4 pathway controls cellular interactions by inducing repulsive or adhesive properties, depending on forward or reverse signaling. Here, we report that in an in vivo metastatic melanoma model, ephrin-B2-mediated activation of EphB4 induces tumor cell repulsion from bone endothelium, translating in reduced spinal bone metastatic loci and improved neurological function. Selective ephrin-B2 depletion in endothelial cells or EphB4 inhibition increases bone metastasis and shortens the time window to hind-limb locomotion deficit from spinal cord compression. EphB4 overexpression in melanoma cells ameliorates the metastatic phenotype and improves neurological outcome. Timely harvesting of bone tissue after tumor cell injection and intravital bone microscopy revealed less tumor cells attached to ephrin-B2-positive endothelial cells. These results suggest that ephrin-B2-EphB4 communication influences bone metastasis formation by altering melanoma cell repulsion/adhesion to bone endothelial cells, and represents a molecular target for therapeutic intervention.
Identifiants
pubmed: 32989254
doi: 10.1038/s41388-020-01473-y
pii: 10.1038/s41388-020-01473-y
doi:
Substances chimiques
NVP-BHG712
0
Pyrazoles
0
Pyrimidines
0
Ephb2 protein, mouse
EC 2.7.10.1
Ephb4 protein, mouse
EC 2.7.10.1
Receptor, EphB2
EC 2.7.10.1
Receptor, EphB4
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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