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Secreted phosphoprotein-1 directly provokes vascular leakage to foster malignant pleural effusion

Abstract

Secreted phosphoprotein-1 (SPP1) promotes cancer cell survival and regulates tumor-associated angiogenesis and inflammation, both central to the pathogenesis of malignant pleural effusion (MPE). Here, we examined the impact of tumor- and host-derived SPP1 in MPE formation and explored the mechanisms by which the cytokine exerts its effects. We used a syngeneic murine model of lung adenocarcinoma-induced MPE. To dissect the effects of tumor- versus host-derived SPP1, we intrapleurally injected wild-type and SPP1-knockout C57/BL/6 mice with either wild-type or SPP1-deficient syngeneic lung cancer cells. We demonstrated that both tumor- and host-derived SPP1 promoted pleural fluid accumulation and tumor dissemination in a synergistic manner (P<0.001). SPP1 of host origin elicited macrophage recruitment into the cancer-affected pleural cavity and boosted tumor angiogenesis, whereas tumor-derived SPP1 curtailed cancer cell apoptosis in vivo. Moreover, the cytokine directly promoted vascular hyper-permeability independently of vascular endothelial growth factor. In addition, SPP1 of tumor and host origin differentially affected the expression of proinflammatory and angiogenic mediators in the tumor microenvironment. These results suggest that SPP1 of tumor and host origin impact distinct aspects of MPE pathobiology to synergistically promote pleural fluid formation and pleural tumor progression. SPP1 may present an attractive target of therapeutic interventions for patients with MPE.

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Acknowledgements

We thank Dr A Marantidou and Z Kollia for professional veterinarian and animal care assistance, respectively. We also thank L Liaw (Maine Medical Center Research Institute) for permission to use the Spp1+/+ and Spp1−/− mice. This work was supported by the ‘Thorax’ Foundation (Athens, Greece) and by a research grant by GlaxoSmithKline (funding 12 000 to IP). GlaxoSmithKline had no involvement in study design, collection, analysis and interpretation of data, writing of the report and in the decision to submit the report for publication. IP and IK had full control of all of the data in this study and take complete responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to I Psallidas.

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Psallidas, I., Stathopoulos, G., Maniatis, N. et al. Secreted phosphoprotein-1 directly provokes vascular leakage to foster malignant pleural effusion. Oncogene 32, 528–535 (2013). https://doi.org/10.1038/onc.2012.57

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