Chronic DLL4 blockade induces vascular neoplasms.
Delta-like 4 (DLL4)-mediated Notch signalling has emerged as an attractive target for cancer therapy. However, the potential side effects of blocking this pathway remain uncertain. Here we show that chronic DLL4 blockade causes pathological activation of endothelial cells, disrupts normal organ homeostasis and induces vascular tumours, raising important safety concerns.
Department of Tumor Biology and Angiogenesis, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. minhong@gene.com
Minhong
M
Yan
Christopher A
CA
Callahan
Joseph C
JC
Beyer
Krishna P
KP
Allamneni
Gu
G
Zhang
John Brady
JB
Ridgway
Kyle
K
Niessen
Greg D
GD
Plowman
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008252:Macaca fascicularis; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D051381:Rats; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D019043:Vascular Neoplasms / Q000139:chemically induced*
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch