title: The promotion of breast cancer metastasis caused by inhibition of CSF-1R/CSF-1 signaling is blocked by targeting the G-CSF receptor.
abstract: Treatment options are limited for patients with breast cancer presenting with metastatic disease. Targeting of tumor-associated macrophages through the inhibition of colony-stimulating factor-1 receptor (CSF-1R), a key macrophage signaling pathway, has been reported to reduce tumor growth and metastasis, and these treatments are now in clinical trials. Here, we report that, surprisingly, treatment with neutralizing anti-CSF-1R and anti-CSF-1 antibodies, or with two different small-molecule inhibitors of CSF-1R, could actually increase spontaneous metastasis without altering primary tumor growth in mice bearing two independently derived mammary tumors. The blockade of CSF-1R or CSF-1 led to increased levels of serum G-CSF, increased frequency of neutrophils in the primary tumor and in the metastasis-associated lung, as well as increased numbers of neutrophils and Ly6C(hi) monocytes in the peripheral blood. Neutralizing antibody against the G-CSF receptor, which regulates neutrophil development and function, reduced the enhanced metastasis and neutrophil numbers that resulted from CSF-1R blockade. These results indicate that the role of the CSF-1R/CSF-1 system in breast cancer is far more complex than originally proposed, and requires further investigation as a therapeutic target.
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne; Department of Medicine, Arthritis and Inflammation Research Centre; and.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Swierczak
authors.affiliation: Department of Medicine, Arthritis and Inflammation Research Centre; and.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cook
authors.affiliation: Department of Medicine, Arthritis and Inflammation Research Centre; and.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Lenzo
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne;
authors.forename: Christina M
authors.initials: CM
authors.lastname: Restall
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne;
authors.forename: Judy P
authors.initials: JP
authors.lastname: Doherty
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, East Melbourne; Sir Peter MacCallum Department of Oncology; Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia robin.anderson@petermac.org.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Anderson
authors.affiliation: Department of Medicine, Arthritis and Inflammation Research Centre; and.
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D007958:Leukocyte Count; D008175:Lung Neoplasms / Q000556:secondary; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000473:pathology*; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000276:immunology*; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000276:immunology*; D015398:Signal Transduction; D013125:Spinal Neoplasms / Q000556:secondary; D047368:Tumor Burden
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D057134:Antibodies, Neutralizing; D011743:Pyrimidines; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor