Integrin beta4 signaling promotes tumor angiogenesis.
Mice carrying a targeted deletion of the signaling portion of the integrin beta4 subunit display drastically reduced angiogenesis in response to bFGF in the Matrigel plug assay and to hypoxia in the retinal neovascularization model. Molecular cytology indicates that alpha6beta4 signaling promotes branching of beta4+ medium- and small-size vessels into beta4- microvessels without exerting a direct effect on endothelial cell proliferation or survival. Signaling studies reveal that alpha6beta4 signaling induces endothelial cell migration and invasion by promoting nuclear translocation of P-ERK and NF-kappaB. Upon subcutaneous implantation of various cancer cells, the mutant mice develop smaller and significantly less vascularized tumors than wild-type controls. These results provide genetic evidence that alpha6beta4 signaling promotes the onset of the invasive phase of pathological angiogenesis and hence identify a novel target for antiangiogenic therapy.
Nikolopoulos
Sotiris N
SN
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Blaikie
Pamela
P
Yoshioka
Toshiaki
T
Guo
Wenjun
W
Giancotti
Filippo G
FG
D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D039161:Integrin alpha6beta4 / Q000502:physiology*; D039663:Integrin beta4 / Q000235:genetics*; D007797:Laminin; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D016612:Paraffin Embedding; D011509:Proteoglycans; D012160:Retina; D015398:Signal Transduction / Q000502:physiology*; D014407:Tumor Cells, Cultured
D004338:Drug Combinations; D039161:Integrin alpha6beta4; D039663:Integrin beta4; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen