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Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons78834

Vlaicu,  Philip
Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78392

Mertins,  Philipp
Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78381

Mayr,  Thomas
Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78233

Knyazev,  Pjotr
Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons78812

Ullrich,  Axel
Ullrich, Axel / Molecular Biology, Max Planck Institute of Biochemistry, Max Planck Society;

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1471-2407-13-197.pdf
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Citation

Vlaicu, P., Mertins, P., Mayr, T., Widschwendter, P., Ataseven, B., Hogel, B., et al. (2013). Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator. BMC CANCER, 13: 197. doi:10.1186/1471-2407-13-197.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0013-B1A6-C
Abstract
Background: Tumor-associated macrophages (TAM) promote malignant progression, yet the repertoire of oncogenic factors secreted by TAM has not been clearly defined. We sought to analyze which EGFR- and STAT3-activating factors are secreted by monocytes/macrophages exposed to tumor cell-secreted factors. Methods: Following exposure of primary human monocytes and macrophages to supernatants of a variety of tumor cell lines, we have analyzed transcript and secreted protein levels of EGFR family ligands and of STAT3 activators. To validate our findings, we have analyzed TAM infiltration levels, systemic and local protein levels as well as clinical data of primary breast cancer patients. Results: Primary human monocytes and macrophages respond to tumor cell-derived factors by secreting EGFR-and STAT3-activating ligands, thus inducing two important oncogenic pathways in carcinoma cells. Tumor cellsecreted factors trigger two stereotype secretory profiles in peripheral blood monocytes and differentiated macrophages: monocytes secrete epiregulin (EREG) and oncostatin-M (OSM), while macrophages secrete heparin-binding EGF-like growth factor (HB-EGF) and OSM. HB-EGF and OSM cooperatively induce tumor cell chemotaxis. HB-EGF and OSM are co-expressed by TAM in breast carcinoma patients, and plasma levels of both ligands correlate strongly. Elevated HB-EGF levels accompany TAM infiltration, tumor growth and dissemination in patients with invasive disease. Conclusions: Our work identifies systemic markers for TAM involvement in cancer progression, with the potential to be developed into molecular targets in cancer therapy.