Wnt Inhibitor Dickkopf-1 as a Target for Passive Cancer Immunotherapy

Nagato Sato,Satoshi Kondo,Eiju Tsuchiya,Junkichi Koinuma,Yusuke Nakamura,Nobuoki Kohno,Atsushi Takano,Haruhiko Nakayama,Nobuhisa Ishikawa,Masato Aragaki,Ken Masuda,Yohei Miyagi,Hiroyuki Ito,Masaki Miyamoto,Yataro Daigo,Takumi Yamabuki

doi:10.1158/0008-5472.can-09-3879

Abstract

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.

Highlights

The concept of specific molecular targeting therapy has been applied to the development of innovative cancer-treatment strategies
Cell lines and tissue samples The human cancer cell lines used in this study were as follows: four NSCLC cell lines (A549, LC319, NCI-H2170, and PC-14), pancreatic cancer cell lines (Capan-1, Capan-2, HPAF-II, KLM-1, KP-1N, Miapaca-2, Panc02.03, Panc08.13, PK-1, PK-59, PK-9, PL45, and SUIT-2), four gastric cancer cell lines (MKN1, MKN45, MKN7, and MKN74), seven hepatocellular carcinoma (HCC) cell lines (HepG2, HUH-6, HUH-7, SNU-398, SNU-423, SNU-449, and SNU-475), four bile duct cancer cell lines (HuCCT1, TFK-1, RBE, and SSP-25), breast cancer cell lines (BT-20, BT-474, BT-549, HCC1143, HCC1500, HCC1937, MCF-7, MDA-MB-157, MDA-MB-231, MDA-MB453, MDA-MB-435S, SK-BR-3, T47D, and ZR-75-1), and two cervical cancer cell lines (C33A and HeLa; Supplementary Table S1)
To examine a possible application of serum DKK1 levels as a diagnostic biomarker for a wide range of human cancers, we first investigated the expression level of DKK1 transcript in cancers derived from the pancreas, stomach, liver, bile duct, mammary gland, and uterus because our gene expression profile analysis implied the transactivation of DKK1 in these tumors

Summary

Introduction

The concept of specific molecular targeting therapy has been applied to the development of innovative cancer-treatment strategies. Two main approaches are available in clinical practice: therapeutic monoclonal antibodies (mAb) and small-molecule agents [1]. There is an increasing interest in the use of antibody-based immunotherapy for the treatment of malignant diseases, and some dramatic clinical responses have enhanced the activity in this field [1]. Rituximab (Rituxan) is the chimeric anti-CD20 antibody that revolutionized lymphoma treatment [2]. Trastuzumab (Herceptin) is the humanized Ab against the human epidermal growth factor receptor (HER)/ERBB2 for the treatment of patients with metastatic breast cancer in which HER/ ERBB2 gene was highly overexpressed [3]. Bevacizumab (Avastin) is the humanized Ab against vascular endothelial

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Conclusion