Wnt inhibitor Dickkopf-1 as a target for passive cancer immunotherapy.
Dickkopf-1 (DKK1) is an inhibitor of Wnt/beta-catenin signaling that is overexpressed in most lung and esophageal cancers. Here, we show its utility as a serum biomarker for a wide range of human cancers, and we offer evidence favoring the potential application of anti-DKK1 antibodies for cancer treatment. Using an original ELISA system, high levels of DKK1 protein were found in serologic samples from 906 patients with cancers of the pancreas, stomach, liver, bile duct, breast, and cervix, which also showed elevated expression levels of DKK1. Additionally, anti-DKK1 antibody inhibited the invasive activity and the growth of cancer cells in vitro and suppressed the growth of engrafted tumors in vivo. Tumor tissues treated with anti-DKK1 displayed significant fibrotic changes and a decrease in viable cancer cells without apparent toxicity in mice. Our findings suggest DKK1 as a serum biomarker for screening against a variety of cancers, and anti-DKK1 antibodies as potential theranostic tools for diagnosis and treatment of cancer.
Sato
Nagato
N
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yamabuki
Takumi
T
Takano
Atsushi
A
Koinuma
Junkichi
J
Aragaki
Masato
M
Masuda
Ken
K
Ishikawa
Nobuhisa
N
Kohno
Nobuoki
N
Ito
Hiroyuki
H
Miyamoto
Masaki
M
Nakayama
Haruhiko
H
Miyagi
Yohei
Y
Tsuchiya
Eiju
E
Kondo
Satoshi
S
Nakamura
Yusuke
Y
Daigo
Yataro
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000276:immunology; D016022:Case-Control Studies; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000097:blood / Q000473:pathology / Q000628:therapy*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors
D057134:Antibodies, Neutralizing; D014408:Biomarkers, Tumor; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins