Breast tumor cells transendothelial migration induces endothelial cell anoikis through extracellular matrix degradation.
Mutual interactions between human breast cancer cells and endothelial cells were studied in a model mimicking tumor cell intravasation. MDA-MB-231 tumor cells and human umbilical vein endothelial cells (HUVEC) were cocultured on opposite sides of a Transwell filter allowing tumor cell contacts with the basement membrane of the HUVEC forming endothelium and tumor cell transendothelial migration. Confocal microscopy analysis showed that transmigrating MDA-MB-231 cells lay under the HUVEC, thereby inducing HUVEC detachment and tumor cell-HUVEC contact-dependent apoptosis. GM6001 a matrix metalloproteinase (MMP) inhibitor inhibited almost completely, the MDA-MB-231 cell transendothelial migration and the anoikis process. In this intravasation model, a tumor cell invasive mechanism was demonstrated (i) induction of extensive endothelial anoikis induced by degradation of the extracellular matrix (ECM) components, (ii) activation of pro-matrix metalloproteinase (MMP)-2 into MMP-2 by the MT1-MMP-TIMP (tissue inhibitor metalloproteinase) 2-pro-MMP-2 membrane complex and (iii) attraction and migration of metastatic cell through apoptotic endothelium. These interactions could partly explain the necrosis-angiogenesis relationship in tumor angiogenesis.
Peyri
Nicole
N
INSERM Unité 553, Hôpital Saint-Louis, F 75475 Paris cedex 10, France.
Berard
Madeleine
M
Fauvel-Lafeve
Françoise
F
Trochon
Veronique
V
Arbeille
Brigitte
B
Lu
He
H
Legrand
Chantal
C
Crepin
Michel
M
D023102:Anoikis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002465:Cell Movement; D002478:Cells, Cultured; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000473:pathology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D020782:Matrix Metalloproteinases; D053511:Matrix Metalloproteinase 14