Anti-oncostatin M antibody inhibits the pro-malignant effects of oncostatin M receptor overexpression in squamous cell carcinoma.
J Pathol
; 244(3): 283-295, 2018 03.
Article
em En
| MEDLINE
| ID: mdl-29205362
ABSTRACT
The oncostatin M (OSM) receptor (OSMR) shows frequent gene copy number gains and overexpression in cervical squamous cell carcinomas (SCCs), associated with adverse clinical outcomes. In SCC cells that overexpress OSMR, the major ligand OSM induces multiple pro-malignant effects, including invasion, secretion of angiogenic factors, and metastasis. Here, we demonstrate, for the first time, that OSMR overexpression in SCC cells activates cell-autonomous feed-forward signalling, via further expression of OSMR and OSM and sustained STAT3 activation, despite expression of the negative regulator suppressor of cytokine signalling 3 (SOCS3). The pro-malignant effects associated with OSMR overexpression are critically mediated by JAK-STAT3 activation, which is induced by exogenous OSM and also by autocrine OSM-OSMR interactions. Importantly, specific inhibition of OSM-OSMR interactions by neutralizing antibodies significantly inhibits STAT3 activation and feed-forward signalling, leading to reduced invasion, angiogenesis, and metastasis. Our findings are supported by data from 1254 clinical SCC samples, in which OSMR levels correlated with multiple cognate genes, including OSM, STAT3, and downstream targets. These data strongly support the development of OSM-OSMR-blocking antibodies as biologically targeted therapies against SCCs of the cervix and other anatomical sites. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neoplasias do Colo do Útero
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Subunidade beta de Receptor de Oncostatina M
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Antineoplásicos Imunológicos
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Carcinoma de Células Escamosas de Cabeça e Pescoço
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Neoplasias de Cabeça e Pescoço
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
J Pathol
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Reino Unido