Anti-oncostatin M antibody inhibits the pro-malignant effects of oncostatin M receptor overexpression in squamous cell carcinoma.
Araujo, Angela M
The Journal of pathology
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Kucia-Tran, J. A., Tulkki, V., Scarpini, C., Smith, S., Wallberg, M., Paez-Ribes, M., Araujo, A. M., et al. (2018). Anti-oncostatin M antibody inhibits the pro-malignant effects of oncostatin M receptor overexpression in squamous cell carcinoma.. The Journal of pathology, 244 (3), 283-295. https://doi.org/10.1002/path.5010
The oncostatin M receptor (OSMR) shows frequent gene copy-number gain and over-expression 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 over-expression 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 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 1,254 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.
Cell Line, Tumor, Animals, Mice, Inbred NOD, Humans, Mice, SCID, Head and Neck Neoplasms, Lung Neoplasms, Xenograft Model Antitumor Assays, Autocrine Communication, Signal Transduction, Gene Expression Regulation, Neoplastic, Up-Regulation, Phosphorylation, Uterine Cervical Neoplasms, Female, STAT3 Transcription Factor, Oncostatin M, Janus Kinase 2, Oncostatin M Receptor beta Subunit, Suppressor of Cytokine Signaling 3 Protein, Antineoplastic Agents, Immunological, Squamous Cell Carcinoma of Head and Neck
Cancer Research UK (13080)
External DOI: https://doi.org/10.1002/path.5010
This record's URL: https://www.repository.cam.ac.uk/handle/1810/273175