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Open Access Highly Accessed Research article

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

Philip Vlaicu1, Philipp Mertins13, Thomas Mayr1, Peter Widschwendter24, Beyhan Ataseven2, Bernhard Högel2, Wolfgang Eiermann2, Pjotr Knyazev1 and Axel Ullrich1*

Author Affiliations

1 Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried 82152, Germany

2 Department of Gynecology and Obstetrics, Red Cross Hospital, Munich 80637, Germany

3 Current address: Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

4 Current address: University Hospital for Women, University of Tuebingen, Tuebingen 72076, Germany

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BMC Cancer 2013, 13:197  doi:10.1186/1471-2407-13-197

Published: 18 April 2013

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 cell-secreted 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.

Keywords:
TAM; Macrophage; Monocyte; Breast; Carcinoma; Patient; EGFR; STAT3; Marker; Progression