Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis.
VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function. Therefore, we considered whether this property of VEGF might contribute to tumor cell extravasation and metastasis. To test this, mice lacking the Src family kinases Src or Yes, which maintain endothelial barrier function in the presence of VEGF, were injected intravenously with VEGF-expressing tumor cells. We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes. At the molecular level, VEGF compromises the endothelial barrier by disrupting a VE-cadherin-beta-catenin complex in lung endothelium from wild-type, but not Yes-deficient, mice. Disrupting the endothelial barrier directly with anti-VE-cadherin both amplifies metastasis in normal mice and overcomes the genetic resistance in Yes-deficient mice. Pharmacological blockade of VEGF, VEGFR-2, or Src stabilizes endothelial barrier function and suppresses tumor cell extravasation in vivo. Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.
Weis
Sara
S
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Cui
Jianhua
J
Barnes
Leo
L
Cheresh
David
D
D000818:Animals; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D008854:Microscopy, Electron; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000473:pathology; D051575:Proto-Oncogene Proteins c-yes; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051176:beta Catenin; D019061:src-Family Kinases / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D003598:Cytoskeletal Proteins; D049452:Green Fluorescent Proteins; D051575:Proto-Oncogene Proteins c-yes; D015534:Trans-Activators; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D051176:beta Catenin; D019061:src-Family Kinases; D000099152:Cadherin 5; C495267:CTNNB1 protein, mouse; C496639:Yes1 protein, mouse