title: Macrophages mediate a switch between canonical and non-canonical Wnt pathways in canine mammary tumors.
abstract: OBJECTIVE
  According to the current hypothesis, tumor-associated macrophages (TAMs) are "corrupted" by cancer cells and subsequently facilitate, rather than inhibit, tumor metastasis. Because the molecular mechanisms of cancer cell-TAM interactions are complicated and controversial we aimed to better define this phenomenon.
  
  
  RESULTS
  Using microRNA microarrays, Real-time qPCR and Western blot we showed that co-culture of canine mammary tumor cells with TAMs or treatment with macrophage-conditioned medium inhibited the canonical Wnt pathway and activated the non-canonical Wnt pathway in tumor cells. We also showed that co-culture of TAMs with tumor cells increased expression of canonical Wnt inhibitors in TAMs. Subsequently, we demonstrated macrophage-induced invasive growth patterns and epithelial-mesenchymal transition of tumor cells. Validation of these results in canine mammary carcinoma tissues (n = 50) and xenograft tumors indicated the activation of non-canonical and canonical Wnt pathways in metastatic tumors and non-metastatic malignancies, respectively. Activation of non-canonical Wnt pathway correlated with number of TAMs.
  
  
  CONCLUSIONS
  We demonstrated that TAMs mediate a "switch" between canonical and non-canonical Wnt signaling pathways in canine mammary tumors, leading to increased tumor invasion and metastasis. Interestingly, similar changes in neoplastic cells were observed in the presence of macrophage-conditioned medium or live macrophages. These observations indicate that rather than being "corrupted" by cancer cells, TAMs constitutively secrete canonical Wnt inhibitors that decrease tumor proliferation and development, but as a side effect, they induce the non-canonical Wnt pathway, which leads to tumor metastasis. These data challenge the conventional understanding of TAM-cancer cell interactions.
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Król
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Mucha
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland ; Department of Animal Environment Biology, Faculty of Animal Sciences, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Majchrzak
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Homa
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Bulkowska
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Alicja
authors.initials: A
authors.lastname: Majewska
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Gajewska
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Pietrzak
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Mikołaj
authors.initials: M
authors.lastname: Perszko
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Romanowska
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland ; Department of Large Animal Diseases with Clinic, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Karol
authors.initials: K
authors.lastname: Pawłowski
authors.affiliation: Area Diagnostica Integrata Istologia e Microscopia Elettronica Istituto Zooprofilattico Sperimentale dell'Umbria e delle Marche, Perugia, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Manuali
authors.affiliation: Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hellmen
authors.affiliation: Department of Physiological Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Motyl
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003599:Cytoskeleton / Q000378:metabolism; D004285:Dogs; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015870:Gene Expression; D064593:Heterografts; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D008954:Models, Biological; D021381:Protein Transport; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D051153:Wnt Proteins; D051176:beta Catenin