Abstract
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.
Highlights
Malignant mesothelioma is a tumor caused primarily by asbestos exposure [1, 2]
Previous studies revealed that normal mesothelial cells in situ express little connective tissue growth factor (CTGF) but mesothelioma cells express high levels of CTGF, which is associated with the malignant characteristics [10, 11]
In the present study, using an orthotopic mouse model, we demonstrated that FG-3019 attenuates mesothelioma growth by inhibiting proliferation and inducing apoptosis of both mesothelioma and stromal cells
Summary
Malignant mesothelioma is a tumor caused primarily by asbestos exposure [1, 2]. Asbestos is recognized as a carcinogen and its use has been legally prohibited in most developed countries. Because it takes 30-40 years to develop mesothelioma after asbestos inhalation, the incidence of mesothelioma is expected to rise in the www.oncotarget.com coming decades [3, 4]. Patients with the sarcomatoid subtype present the poorest prognosis with remarkably short survival [7]. It is necessary to understand the molecular mechanisms that regulate mesothelial carcinogenesis [8, 9] and mesothelioma progression [10], and to develop molecularly targeted drugs to improve the patients’ prognosis
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