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 Sahni, Patricia J. Simpson-Haidaris

Research output: Contribution to journalArticle

32 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Transendothelial and Transepithelial Migration
Fibrinogen
Permeability
Breast
Epithelial Cells
Breast Neoplasms
cadherin 5
Fibrin
Endothelial Cells
Lymphatic Metastasis
Umbilical Veins
Cell Adhesion Molecules

Keywords

  • Endothelial permeability
  • Fibrinogen
  • Inflammatory breast cancer
  • Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The VE-cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells. / Sahni, Abha; Aŕevalo, Maria T.; Sahni, Sanjeev; Simpson-Haidaris, Patricia J.

In: International Journal of Cancer, Vol. 125, No. 3, 01.08.2009, p. 577-584.

Research output: Contribution to journalArticle

@article{0c251a1daa3749e384dc8c460367204a,
title = "The VE-cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells",
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.",
keywords = "Endothelial permeability, Fibrinogen, Inflammatory breast cancer, Metastasis",
author = "Abha Sahni and Aŕevalo, {Maria T.} and Sanjeev Sahni and Simpson-Haidaris, {Patricia J.}",
year = "2009",
month = "8",
day = "1",
doi = "10.1002/ijc.24340",
language = "English (US)",
volume = "125",
pages = "577--584",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",
number = "3",

}

TY - JOUR

T1 - The VE-cadherin binding domain of fibrinogen induces endothelial barrier permeability and enhances transendothelial migration of malignant breast epithelial cells

AU - Sahni, Abha

AU - Aŕevalo, Maria T.

AU - Sahni, Sanjeev

AU - Simpson-Haidaris, Patricia J.

PY - 2009/8/1

Y1 - 2009/8/1

N2 - 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.

AB - 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.

KW - Endothelial permeability

KW - Fibrinogen

KW - Inflammatory breast cancer

KW - Metastasis

UR - http://www.scopus.com/inward/record.url?scp=67650095394&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67650095394&partnerID=8YFLogxK

U2 - 10.1002/ijc.24340

DO - 10.1002/ijc.24340

M3 - Article

VL - 125

SP - 577

EP - 584

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 3

ER -