title: In situ proliferation contributes to accumulation of tumor-associated macrophages in spontaneous mammary tumors.
abstract: Infiltration of a neoplasm with tumor-associated macrophages (TAMs) is considered an important negative prognostic factor and is functionally associated with tumor vascularization, accelerated growth, and dissemination. However, the ontogeny and differentiation pathways of TAMs are only incompletely characterized. Here, we report that intense local proliferation of fully differentiated macrophages rather than low-pace recruitment of blood-borne precursors drives TAM accumulation in a mouse model of spontaneous mammary carcinogenesis, the MMTVneu strain. TAM differentiation and expansion is regulated by CSF1, whose expression is directly controlled by STAT1 at the gene promoter level. These findings appear to be also relevant for human breast cancer, in which an interrelationship between STAT1, CSF1, and macrophage marker expression was identified. We propose that, akin to various MU subtypes in nonmalignant tissues, local proliferation and CSF1 play a vital role in the homeostasis of TAMs.
authors.affiliation: Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria; Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Piotr
authors.initials: P
authors.lastname: Tymoszuk
authors.forename: Hanneke
authors.initials: H
authors.lastname: Evens
authors.forename: Vanessa
authors.initials: V
authors.lastname: Marzola
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wachowicz
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Wasmer
authors.forename: Sebak
authors.initials: S
authors.lastname: Datta
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Müller-Holzner
authors.forename: Heidi
authors.initials: H
authors.lastname: Fiegl
authors.forename: Günther
authors.initials: G
authors.lastname: Böck
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Doppler
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D050794:STAT1 Transcription Factor; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor
keywords: CSF1; In situ proliferation; STAT1; Tumor-associated macrophages