Targeting of VEGF-dependent transendothelial migration of cancer cells by bevacizumab.
Cancer progression is often associated with the formation of malignant effusions. Vascular endothelial growth factor (VEGF) is a major regulator of vascular permeability and has been implicated as mediator of tumor progression. We examined the production and secretion of VEGF(165) in various primary cancer cells derived from malignant effusions, and the role of exogenous VEGF(165) as a mediator of effusion formation. VEGF(165) was constantly secreted by all cultured tumor cells in an mTOR-dependent manner, as it was inhibited by the mTOR inhibitor rapamycin. Secreted VEGF(165) showed functional activity by inducing endothelial leakiness and tumor cell-transendothelial migration in vitro, effects which could be reverted by the anti-VEGF antibody bevacizumab. Thus, mTOR inhibitors as well as bevacizumab should be considered as potential agents in cancer patients suffering from malignant effusions.
Prager
Gerald W
GW
Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, A-1090 Vienna, Austria.
Lackner
Eva-Maria
EM
Krauth
Maria-Theresa
MT
Unseld
Matthias
M
Poettler
Marina
M
Laffer
Sylvia
S
Cerny-Reiterer
Sabine
S
Lamm
Wolfgang
W
Kornek
Gabriela V
GV
Binder
Bernd R
BR
Zielinski
Christoph C
CC
Valent
Peter
P
D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis / Q000187:drug effects; D000068258:Bevacizumab; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004727:Endothelium / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047908:Intracellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus