Blocking neuropilin-2 function inhibits tumor cell metastasis.
Metastasis, which commonly uses lymphatics, accounts for much of the mortality associated with cancer. The vascular endothelial growth factor (VEGF)-C coreceptor, neuropilin-2 (Nrp2), modulates but is not necessary for developmental lymphangiogenesis, and its significance for metastasis is unknown. An antibody to Nrp2 that blocks VEGFC binding disrupts VEGFC-induced lymphatic endothelial cell migration, but not proliferation, in part independently of VEGF receptor activation. It does not affect established lymphatics in normal adult mice but reduces tumoral lymphangiogenesis and, importantly, functional lymphatics associated with tumors. It also reduces metastasis to sentinel lymph nodes and distant organs, apparently by delaying the departure of tumor cells from the primary tumor. Our results demonstrate that Nrp2, which was originally identified as an axon-guidance receptor, is an attractive target for modulating metastasis.
Caunt
Maresa
M
Tumor Biology and Angiogenesis, Genentech, Inc., South San Francisco, CA 94080, USA.
Mak
Judy
J
Liang
Wei-Ching
WC
Stawicki
Scott
S
Pan
Qi
Q
Tong
Raymond K
RK
Kowalski
Joe
J
Ho
Calvin
C
Reslan
Hani Bou
HB
Ross
Jed
J
Berry
Leanne
L
Kasman
Ian
I
Zlot
Constance
C
Cheng
Zhiyong
Z
Le Couter
Jennifer
J
Filvaroff
Ellen H
EH
Plowman
Greg
G
Peale
Franklin
F
French
Dorothy
D
Carano
Richard
R
Koch
Alexander W
AW
Wu
Yan
Y
Watts
Ryan J
RJ
Tessier-Lavigne
Marc
M
Bagri
Anil
A
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000918:Antibody Specificity / Q000187:drug effects; D001435:Bacteriophages; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D042583:Lymphangiogenesis / Q000187:drug effects; D008207:Lymphatic Metastasis / Q000517:prevention & control; D008208:Lymphatic System / Q000187:drug effects / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009369:Neoplasms / Q000473:pathology*; D039943:Neuropilin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D019138:Antibodies, Blocking; D039943:Neuropilin-2; D042582:Vascular Endothelial Growth Factor C; D040262:Receptors, Vascular Endothelial Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2