title: Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator.
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.
authors.affiliation: Department of Molecular Biology, Max Planck Institute of Biochemistry, Martinsried 82152, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Vlaicu
authors.forename: Philipp
authors.initials: P
authors.lastname: Mertins
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayr
authors.forename: Peter
authors.initials: P
authors.lastname: Widschwendter
authors.forename: Beyhan
authors.initials: B
authors.lastname: Ataseven
authors.forename: Bernhard
authors.initials: B
authors.lastname: Högel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Eiermann
authors.forename: Pjotr
authors.initials: P
authors.lastname: Knyazev
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
mesh_terms: D001943:Breast Neoplasms / Q000097:blood* / Q000473:pathology; D002277:Carcinoma / Q000097:blood* / Q000556:secondary; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002633:Chemotaxis; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066260:Epiregulin; D005260:Female; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D053683:Oncostatin M / Q000378:metabolism*; D019899:Paracrine Communication; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: C587880:EREG protein, human; D066260:Epiregulin; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053683:Oncostatin M; D004815:Epidermal Growth Factor