title: Canine mammary cancer cells direct macrophages toward an intermediate activation state between M1/M2.
abstract: BACKGROUND
  Canine mammary carcinoma is the most common cancer in female dogs and is often fatal due to the development of distance metastasis. The microenvironment of a tumour often contains abundant infiltrates of macrophages called tumour-associated macrophages (TAMs). TAMs express an activated phenotype, termed M2, which sustains proliferation of cancer cells, and has been correlated with poor clinical outcomes in human cancer patients. Cancer cells themselves have been implicated in stimulating the conversion of macrophages to a TAM with an M2 phenotype. This process has yet to be fully elucidated. Here we investigate the interplay between cancer cells and macrophages in the context of canine mammary carcinoma.
  
  
  RESULTS
  We show that cancer cells inhibit lipopolysaccharide (LPS)-induced macrophage activation. Further, we show that macrophage associated proteins, colony-stimulating factor (CSF)-1 and C-C motif ligand (CCL)-2, stimulate macrophages and are responsible for the effects of cancer cells on macrophages. We suggest the existence of a feedback loop between macrophages and cancer cells; while cancer cells influence the phenotype of the TAMs through CSF-1 and CCL2, the macrophages induce canine mammary cancer cells to upregulate their own expression of the receptors for CSF-1 and CCL2 and increase the cancer cellular metabolic activity. However, these cytokines in isolation induce a phenotypic state in macrophages that is between M1 and M2 phenotypes.
  
  
  CONCLUSIONS
  Overall, our results demonstrate the extent to which canine mammary carcinoma cells influence the macrophage phenotype and the relevance of a feedback loop between these cells, involving CSF-1 and CCL2 as important mediators.
authors.affiliation: The Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Scotland, EH25 9RG, UK. breno.beirao@roslin.ed.ac.uk.
authors.forename: Breno C B
authors.initials: BC
authors.lastname: Beirão
authors.affiliation: The Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Scotland, EH25 9RG, UK. teresa.raposo@roslin.ed.ac.uk.|Department of Veterinary Sciences, Universidade de Trás-os-Montes e Alto Douro, 5001-801, Vila Real, Portugal. teresa.raposo@roslin.ed.ac.uk.
authors.forename: Teresa
authors.initials: T
authors.lastname: Raposo
authors.affiliation: The Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Scotland, EH25 9RG, UK. lisa.pang@roslin.ed.ac.uk.
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Pang
authors.affiliation: The Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Scotland, EH25 9RG, UK. david.argyle@roslin.ed.ac.uk.
authors.forename: David J
authors.initials: DJ
authors.lastname: Argyle
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004283:Dog Diseases / Q000473:pathology*; D004285:Dogs; D005260:Female; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000494:pharmacology; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D008262:Macrophage Activation / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D015674:Mammary Neoplasms, Animal / Q000473:pathology*; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D051879:Twist-Related Protein 1; D016173:Macrophage Colony-Stimulating Factor