Amino‐terminal fragments of laminin γ2 chain retract vascular endothelial cells and increase vascular permeability

Laminin γ2 (Lmγ2) chain, a subunit of laminin‐332, is a typical molecular marker of invading cancer cells, and its expression correlates with poor prognosis of cancer patients. It was previously found that forced expression of Lmγ2 in cancer cells promotes their invasive growth in nude mice. However...

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Published in:Cancer science 2014-02, Vol.105 (2), p.168-175
Main Authors: Sato, Hiroki, Oyanagi, Jun, Komiya, Eriko, Ogawa, Takashi, Higashi, Shouichi, Miyazaki, Kaoru
Format: Article
Language:English
Subjects:
Actin
AKT protein
Animals
Antibiotics
Antigens, CD - metabolism
beta Catenin - metabolism
Cadherins
Cadherins - metabolism
Cancer
Capillary Permeability - physiology
Cell adhesion & migration
Cell culture
Cell Line, Tumor
Cell migration
Cell Movement - physiology
Cytoskeleton
Cytoskeleton - metabolism
Cytoskeleton - pathology
Cytoskeleton - physiology
Endothelial cells
Endothelial Cells - metabolism
Endothelial Cells - physiology
Endothelium, Vascular - metabolism
Endothelium, Vascular - pathology
Endothelium, Vascular - physiology
Epidermal growth factor
Epidermal Growth Factor - metabolism
Fibroblasts
Heparan sulfate
Heparan sulfate proteoglycans
Human Umbilical Vein Endothelial Cells
Humans
Immunoglobulins
Intercellular Junctions - metabolism
Intercellular Junctions - pathology
Intercellular Junctions - physiology
Invasiveness
Kinases
Laboratory animals
Laminin
Laminin - metabolism
Laminin - pharmacology
Laminin γ2 chain
laminin‐332
MAP kinase
MAP Kinase Signaling System - physiology
Membranes
Metastasis
Mice
Mice, Inbred BALB C
Motility
Original
p38 Mitogen-Activated Protein Kinases - metabolism
Permeability
Proteins
Proteoglycans
Proteolysis
Proto-Oncogene Proteins c-akt - metabolism
Recombinant Proteins - pharmacology
Studies
tumor invasion
Urinary Bladder Neoplasms - metabolism
Urinary Bladder Neoplasms - pathology
vascular endothelial cells
vascular permeability
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Summary:Laminin γ2 (Lmγ2) chain, a subunit of laminin‐332, is a typical molecular marker of invading cancer cells, and its expression correlates with poor prognosis of cancer patients. It was previously found that forced expression of Lmγ2 in cancer cells promotes their invasive growth in nude mice. However, the mechanism of the tumor‐promoting activity of Lmγ2 remains unknown. Here we investigated the interaction between Lmγ2 and vascular endothelial cells. When treated with an N‐terminal proteolytic fragment of γ2 (γ2pf), HUVECs became markedly retracted or shrunken. The overexpression of Lmγ2 or treatment with γ2pf stimulated T‐24 bladder carcinoma cells to invade into the HUVEC monolayer and enhanced their transendothelial migration in vitro. Moreover, γ2pf increased endothelial permeability in vitro and in vivo. As the possible mechanisms, γ2pf activated ERK and p38 MAPK but inactivated Akt in HUVECs. Such effects of γ2pf led to prominent actin stress fiber formation in HUVECs, which was blocked by a ROCK inhibitor. In addition, γ2pf induced delocalization of VE‐cadherin and β‐catenin from the intercellular junction. As possible receptors, γ2pf interacted with heparan sulfate proteoglycans on the surface of HUVECs. Moreover, we localized the active site of γ2pf to the N‐terminal epidermal growth factor‐like repeat. These data suggest that the interaction between γ2pf and heparan sulfate proteoglycans induces cytoskeletal changes of endothelial cells, leading to the loss of endothelial barrier function and the enhanced transendothelial migration of cancer cells. These activities of Lmγ2 seem to support the aberrant growth of cancer cells. An N‐terminal fragment of the laminin gamma2 chain retracts vascular endothelial cells by inducing delocalization of VE‐cadherin.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.12323