Vasculotide reduces endothelial permeability and tumor cell extravasation in the absence of binding to or agonistic activation of Tie2.
EMBO Mol Med
; 7(6): 770-87, 2015 Jun.
Article
en En
| MEDLINE
| ID: mdl-25851538
ABSTRACT
Angiopoietin-1 (Ang1) activation of Tie2 receptors on endothelial cells (ECs) reduces adhesion by tumor cells (TCs) and limits junctional permeability to TC diapedesis. We hypothesized that systemic therapy with Vasculotide (VT)-a purported Ang1 mimetic, Tie2 agonist-can reduce the extravasation of potentially metastatic circulating TCs by similarly stabilizing the host vasculature. In vitro, VT and Ang1 treatments impeded endothelial hypermeability and the transendothelial migration of MDA-MB-231âLM2-4 (breast), HT29 (colon), or SN12 (renal) cancer cells to varying degrees. In mice, VT treatment inhibited the transit of TCs through the pulmonary endothelium, but not the hepatic or lymphatic endothelium. In the in vivo LM2-4 model, VT monotherapy had no effect on primary tumors, but significantly delayed distant metastatic dissemination to the lungs. In the post-surgical adjuvant treatment setting, VT therapeutically complemented sunitinib therapy, an anti-angiogenic tyrosine kinase inhibitor which limited the local growth of residual disease. Unexpectedly, detailed investigations into the putative mechanism of action of VT revealed no evidence of Tie2 agonism or Tie2 binding; alternative mechanisms have yet to be determined.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Células Endoteliales
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Receptor TIE-2
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Angiopoyetina 1
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Migración Transendotelial y Transepitelial
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Metástasis de la Neoplasia
Límite:
Animals
Idioma:
En
Revista:
EMBO Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2015
Tipo del documento:
Article
País de afiliación:
Canadá