HGF/scatter factor selectively promotes cell invasion by increasing integrin avidity.
Hepatocyte growth factor/scatter factor (HGF/SF) controls a genetic program known as 'invasive growth', which involves as critical steps cell adhesion, migration, and trespassing of basement membranes. We show here that in MDA-MB-231 carcinoma cells, these steps are elicited by HGF/SF but not by epidermal growth factor (EGF). Neither factor substantially alters the production or activity of extracellular matrix proteases. HGF/SF, but not EGF, selectively promotes cell adhesion on laminins 1 and 5, fibronectin, and vitronectin through a PI3-K-dependent mechanism. Increased adhesion is followed by enhanced invasiveness through isolated matrix proteins as well as through reconstituted basement membranes. Inhibition assays using function-blocking antibodies show that this phenomenon is mediated by multiple integrins including beta1, beta3, beta4, and beta5. HGF/SF triggers clustering of all these integrins at actin-rich adhesive sites and lamellipodia but does not quantitatively modify their membrane expression. These data suggest that HGF/SF promotes cell adhesion and invasiveness by increasing the avidity of integrins for their specific ligands.
Trusolino
L
L
Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo-Torino, Italy. cboccaccio@ircc.unito.it
Cavassa
S
S
Angelini
P
P
Andó
M
M
Bertotti
A
A
Comoglio
P M
PM
Boccaccio
C
C
D000199:Actins / Q000187:drug effects / Q000378:metabolism; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001485:Basement Membrane / Q000737:chemistry / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D003094:Collagen / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008024:Ligands; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D000199:Actins; D000906:Antibodies; D015820:Cadherins; D003094:Collagen; D004338:Drug Combinations; D004815:Epidermal Growth Factor; D016326:Extracellular Matrix Proteins; D017228:Hepatocyte Growth Factor; D016023:Integrins; D007797:Laminin; D008024:Ligands; D020780:Matrix Metalloproteinase 9; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans; D014568:Urokinase-Type Plasminogen Activator; C059485:matrigel