Abstract 2816: Oncostatin M is a proinflammatory cytokine capable of exerting long term biological effects via its binding to ECM components in a bioactive conformation.
Authors: Randall E. Ryan, Bryan Martin, Liliana Mellor, Owen McDougal, Julia Oxford, Cheryl Jorcyk
Journal: Cancer Research (2013)

Abstract Oncostatin M (OSM) is a proinflammatory cytokine that has been reported to promote a metastatic phenotype in cancer cells via its effects on cell proliferation, attachment, migration, invasion and the epithelial to mesenchymal transition. Full length OSM is expressed as a 26 kDa MW species that can be proteolytically processed into a 22 kDa truncated species, via removal of a hydrophilic C-terminal peptide. The extracellular matrix (ECM) acts as a reservoir of biologically active molecules and as a storage site for cell signaling molecules. Many interactions between ECM proteins and cytokines are highly specific and the binding of cytokines to ECM is reported to regulate their distribution, activation and presentation to cells. In the current study, the ability of full length versus truncated OSM to bind to ECM molecules was examined, as well as the effects of immobilized OSM on T-47D and ZR-75-1 breast carcinoma cell signaling and morphology. Both full length and truncated OSM were observed to bind to the ECM components collagen-1, collagen-11, laminin and fibronectin. At least two distinct binding sites were apparent for OSM binding to ECM proteins. Full length 26 kDa OSM was observed to bind ECM to a greater extent at neutral pH than truncated 22 kDa OSM, which indicated a role for the C-terminal region of OSM in ECM binding. Under acidic conditions (pH 5.5) similar amounts of full length versus truncated OSM bound to ECM, which indicated binding independent of the C-terminal tail of OSM. Electrostatic interactions appeared to mediate OSM binding to ECM, since greater binding of 26 kDa and 22 kDa to ECM was observed at pH 5.5 versus pH 7.5 and a slow detachment of OSM bound to ECM at pH 5.5 was observed when the pH was raised to neutral. OSM bound to ECM was observed to be protected from cleavage by tumor-associated proteases, when compared to proteolysis of unbound OSM, which suggested a stabilizing effect on OSM. Importantly, OSM bound to ECM was demonstrated to be biologically active and able to induce pSTAT3 and other OSM associated proteins in T-47D and ZR-75-1 breast carcinoma cells, in vitro. The induction of pSTAT3 could be inhibited with an OSM neutralizing antibody indicating that the ECM binding sites were distinct from the OSM receptor binding site. In addition, OSM bound to ECM was observed to induce morphological changes in T-47D breast cancer cells that included the formation of invadapodia. Taken together, this data suggests an important role for OSM bound to ECM in tumor metastasis, as well as in the acquisition of chronic inflammation and provides additional evidence for the role of inflammatory processes in cancer. Citation Format: Randall E. Ryan, Bryan Martin, Liliana Mellor, Owen McDougal, Julia Oxford, Cheryl Jorcyk. Oncostatin M is a proinflammatory cytokine capable of exerting long term biological effects via its binding to ECM components in a bioactive conformation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2816. doi:10.1158/1538-7445.AM2013-2816