Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model
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Yuuki Ohara1, Shan Hwu Chew1, Nobuaki Misawa1, Shenqi Wang1, Daiki Somiya1, Kae Nakamura2, Hiroaki Kajiyama2, Fumitaka Kikkawa2, Yuta Tsuyuki3, Li Jiang1, Kyoko Yamashita1, Yoshitaka Sekido4, Kenneth E. Lipson5 and Shinya Toyokuni1,6
1Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
2Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
3Department of Pathology and Laboratory Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
4Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan
5FibroGen, Inc., San Francisco, CA 94158, USA
6Sydney Medical School, The University of Sydney, Sydney 2006, Australia
Shinya Toyokuni, email: [email protected]
Keywords: connective tissue growth factor (CTGF); malignant mesothelioma; molecular target therapy; FG-3019 (pamrevlumab); tumor microenvironment
Received: October 31, 2017 Accepted: March 09, 2018 Published: April 06, 2018
Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG-3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma.
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