The VE-cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells.
Int J Cancer
; 125(3): 577-84, 2009 Aug 01.
Article
in En
| MEDLINE
| ID: mdl-19358279
ABSTRACT
Fibrin deposition and exudation of plasma fibrinogen (Fg) have long been recognized as hallmarks of inflammation, cardiovascular disease and neoplasia. The Fg-beta(15-42) domain binds to the endothelial cell adhesion molecule, VE-cadherin, promoting endothelial cell proliferation, angiogenesis and leukocyte diapedesis. Furthermore, spontaneous blood-borne and lymphatic metastasis of some types of tumor emboli requires plasma fibrin(ogen); however, the molecular mechanisms by which this occurs are poorly understood. We sought to determine whether Fg-beta(15-42) and VE-cadherin binding interactions promote endothelial barrier permeability and breast cancer cell transendothelial migration (TEM) using transwell insert culture systems. Synthetic peptides containing/missing residues beta(15-17) critical for Fg-beta(15-42) binding to VE-cadherin, and antibodies that bind to Fg-beta(15-21) (T2G1) and VE-cadherin (BV9) were used to induce or inhibit Fg-mediated permeability and TEM. Fg induced dose-dependent permeability of human umbilical vein and microvascular endothelial but not epithelial cell barriers. Maximal Fg-induced endothelial permeability required Fg-beta(15-42) and VE-cadherin-binding interactions involving Fg-beta(15-17). Fg-induced TEM of malignant MDA-MB-231 and MCF-7 breast cancer cells also required Fg-beta(15-42) and VE-cadherin binding; however, such TEM was independent of E-cadherin or estrogen receptor expression. In contrast, Fg did not induce TEM of nonmalignant MCF-10A breast epithelial cells. Fg-induced endothelial permeability was retained in the presence of MDA-MB-231 but inhibited in the presence of MCF-10A cells. It is intriguing to speculate that loss of Fg-beta(15-42) binding by premalignant breast epithelial cells serves as a molecular switch to induce a highly aggressive, metastatic breast cancer phenotype. Hence, Fg-beta(15-42) represents a potential molecular target for therapeutic intervention of breast cancer metastasis.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Breast Neoplasms
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Fibrinogen
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Endothelium, Vascular
/
Antigens, CD
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Cadherins
/
Endothelial Cells
Limits:
Female
/
Humans
Language:
En
Journal:
Int J Cancer
Year:
2009
Document type:
Article
Affiliation country:
United States