Membrane-type 4 matrix metalloproteinase (MT4-MMP) induces lung metastasis by alteration of primary breast tumour vascular architecture.
The present study aims at investigating the mechanism by which membrane-type 4 matrix metalloproteinase (MT4-MMP), a membrane-anchored MMP expressed by human breast tumour cells promotes the metastatic dissemination into lung. We applied experimental (intravenous) and spontaneous (subcutaneous) models of lung metastasis using human breast adenocarcinoma MDA-MB-231 cells overexpressing or not MT4-MMP. We found that MT4-MMP does not affect lymph node colonization nor extravasation of cells from the bloodstream, but increases the intravasation step leading to metastasis. Ultrastructural and fluorescent microscopic observations coupled with automatic computer-assisted quantifications revealed that MT4-MMP expression induces blood vessel enlargement and promotes the detachment of mural cells from the vascular tree, thus causing an increased tumour vascular leak. On this basis, we propose that MT4-MMP promotes lung metastasis by disturbing the tumour vessel integrity and thereby facilitating tumour cell intravasation.
Chabottaux
Vincent
V
Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Cancer, University of Liege, Tour de Pathologie, Liège, Belgium.
Ricaud
Stéphanie
S
Host
Laurent
L
Blacher
Silvia
S
Paye
Alexandra
A
Thiry
Marc
M
Garofalakis
Anikitos
A
Pestourie
Carine
C
Gombert
Karine
K
Bruyere
Françoise
F
Lewandowsky
Daniel
D
Tavitian
Bertrand
B
Foidart
Jean-Michel
JM
Duconge
Frédéric
F
Noel
Agnès
A
D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary; D008207:Lymphatic Metastasis; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000201:enzymology / Q000473:pathology; D053515:Matrix Metalloproteinase 17 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000378:metabolism
D053515:Matrix Metalloproteinase 17