The VE-cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells

Abha Sahni, Maria T. Aŕevalo, Sanjeev K. Sahni, Patricia J. Simpson-Haidaris

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Fibrin deposition and exudation of plasma fibrinogen (Fg) have long been recognized as hallmarks of inflammation, cardiovascular disease and neoplasia. The Fg-β15-42 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-β15-42 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 β15-17 critical for Fg-β15-42 binding to VE-cadherin, and antibodies that bind to Fg-β15-21 (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-β15-42 and VE-cadherin-binding interactions involving Fg-β15-17. Fg-induced TEM of malignant MDA-MB-231 and MCF-7 breast cancer cells also required Fg-β15-42 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-β15-42 binding by premalignant breast epithelial cells serves as a molecular switch to induce a highly aggressive, metastatic breast cancer phenotype. Hence, Fg-β15-42 represents a potential molecular target for therapeutic intervention of breast cancer metastasis.

Original languageEnglish (US)
Pages (from-to)577-584
Number of pages8
JournalInternational Journal of Cancer
Volume125
Issue number3
DOIs
StatePublished - Aug 1 2009

Keywords

  • Endothelial permeability
  • Fibrinogen
  • Inflammatory breast cancer
  • Metastasis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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