Breast Cancer Cells Stimulate Neutrophils to Produce Oncostatin M: Potential Implications for Tumor Progression

Tumor-associated and tumor-infiltrating neutrophils (TAN) and macrophages (TAM) can account for as much as 50% of the total tumor mass in invasive breast carcinomas. It is thought that tumors secrete factors that elicit a woundrepair response from TAMs and TANs and that this response inadvertently stimulates tumor progression. Oncostatin M is a pleiotropic cytokine belonging to the interleukin-6 family that is expressed by several cell types including activated human T lymphocytes, macrophages, and neutrophils. Whereas oncostatin M can inhibit the proliferation of breast cancer cells in vitro, recent studies suggest that oncostatin M may promote tumor progression by enhancing angiogenesis and metastasis. In addition, neutrophils can be stimulated to synthesize and rapidly release large quantities of oncostatin M. In this article, we show that human neutrophils secrete oncostatin M when cocultured with MDA-MB-231 and T47D human breast cancer cells. Neutrophils isolated from whole blood or breast cancer cells alone express little oncostatin M by immunocytochemistry and ELISA, but neutrophils express and release high levels of oncostatin M when they are cocultured with breast cancer cells. In addition, we show that granulocyte-macrophage colony-stimulating factor produced by breast cancer cells and cell-cell contact are both necessary for the release of oncostatin M from neutrophils. Importantly, neutrophilderived oncostatin M induces vascular endothelial growth factor from breast cancer cells in coculture and increases breast cancer cell detachment and invasive capacity, suggesting that neutrophils and oncostatin M may promote tumor progression in vivo

Breast Cancer Cells Stimulate Neutrophils to Produce Ocostatin M: Potential Implications for Tumor Progression

Human neutrophils secrete, from their granules, a wide range of cytokines (IL-1α, TNF-α, and OSM) which have the capacity to direct the progress of an inflammatory reaction by influencing the activity of immune cells and tissues. Tumor-associated and tumor-infiltrating neutrophils (TANs) and macro phages (TAMs) account for as much as 50% of the total tumor mass in invasive breast carcinomas. It is thought that tumors secrete factors that elicit a wound-repair response from TAMs and TANs, and that this response inadvertently stimulates tumor progression. Oncostatin M (OSM) is a pleiotropic cytokine belonging to the interleukin-6 family and is expressed by several cell types including, activated human T-Iymphocytes, macrophages, and neutrophils. Recent evidence suggests that OSM may promote tumor progression by enhancing angiogenesis and metastasis. It has been shown that neutrophils can be stimulated to synthesize and rapidly release large quantities of the cytokine OSM. We show that human neutrophils secrete OSM when co-cultured with human breast cancer cells (MDA-MB-231 and T47D). Neutrophils isolated from whole blood or breast cancer cells alone express little OSM by immunohistochemistry and ELISA, but when co-cultured, neutrophils express and release high levels of OSM. We also show that breast cancer secreted granulocyte-macrophage colony- stimulating factor (GM-CSF) is important for the increase in neutrophil expressed OSM, and cell-to-cell contact is needed for the granular release of neutrophil-derived OSM. Importantly, neutrophil-derived OSM induces increased levels of vascular endothelial growth factor (VEGF) in co-culture and facilitates an increase in breast cancer cell detachment and invasive capacity. The role of neutrophils in inflammation and tumor progression suggests the possibility of anti-OSM cancer therapies effective against aggressive breast cancers such as inflammatory breast cancer, which has a poor diagnosis and survival rate

Additional file 28 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 28: Table S18. Sex-participation association of the variants with significant sex-specific lipid results

Additional file 17 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 17: Table S9. PheWAS UKB-MVP meta-analysis results for each index lipid variant at Bonferroni threshold for multiple testing

Additional file 33 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 33: Table S22. Mouse genes with lipid phenotypes (silver set)

Additional file 27 of Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Additional file 27: Table S17. Sex-stratified effect sizes in UK Biobank considering all individuals or only those not on cholesterol lowering medications