Anti‐oncostatin M antibody inhibits the pro‐malignant effects of oncostatin M receptor overexpression in squamous cell carcinoma

• Published in: The Journal of pathology 2018-03, Vol.244 (3), p.283-295
• Main Authors: Kucia‐Tran, Justyna A, Tulkki, Valtteri, Scarpini, Cinzia G, Smith, Stephen, Wallberg, Maja, Paez‐Ribes, Marta, Araujo, Angela M, Botthoff, Jan, Feeney, Maria, Hughes, Katherine, Caffarel, Maria M, Coleman, Nicholas
• Format: Article
• Language: English
• Subjects: Activation; Angiogenesis; Animals; Antineoplastic Agents, Immunological - pharmacology; Autocrine Communication; Autocrine signalling; Blocking antibodies; Cell Line, Tumor; Cervical carcinoma; Cervix; Copy number; Female; Gene Expression Regulation, Neoplastic; head and neck; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Metastases; Metastasis; Mice, Inbred NOD; Mice, SCID; neutralizing antibodies; Oncostatin M; Oncostatin M - genetics; Oncostatin M - metabolism; oncostatin M receptor; Oncostatin M Receptor beta Subunit - antagonists & inhibitors; Oncostatin M Receptor beta Subunit - genetics; Oncostatin M Receptor beta Subunit - immunology; Oncostatin M Receptor beta Subunit - metabolism; Phosphorylation; Secretion; Signal Transduction; SOCS-3 protein; Squamous cell carcinoma; Squamous Cell Carcinoma of Head and Neck - drug therapy; Squamous Cell Carcinoma of Head and Neck - immunology; Squamous Cell Carcinoma of Head and Neck - metabolism; Squamous Cell Carcinoma of Head and Neck - pathology; STAT3; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 3 Protein - genetics; Suppressor of Cytokine Signaling 3 Protein - metabolism; Up-Regulation; Uterine Cervical Neoplasms - drug therapy; Uterine Cervical Neoplasms - immunology; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Xenograft Model Antitumor Assays
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.5010

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.