title: Macrophage traits in cancer cells are induced by macrophage-cancer cell fusion and cannot be explained by cellular interaction.
abstract: BACKGROUND
  Cell fusion is a natural process in normal development and tissue regeneration. Fusion between cancer cells and macrophages generates metastatic hybrids with genetic and phenotypic characteristics from both maternal cells. However, there are no clinical markers for detecting cell fusion in clinical context. Macrophage-specific antigen CD163 expression in tumor cells is reported in breast and colorectal cancers and proposed being caused by macrophages-cancer cell fusion in tumor stroma. The purpose of this study is to examine the cell fusion process as a biological explanation for macrophage phenotype in breast.
  
  
  METHODS
  Monocytes, harvested from male blood donor, were activated to M2 macrophages and co-cultured in ThinCert transwell system with GFP-labeled MCF-7 cancer cells. MCF7/macrophage hybrids were generated by spontaneous cell fusion, isolated by fluorescence-activated cell sorting and confirmed by fluorescence microscopy, short tandem repeats analysis and flow cytometry. CD163 expression was evaluated in breast tumor samples material from 127 women by immunohistochemistry.
  
  
  RESULTS
  MCF-7/macrophage hybrids were generated spontaneously at average rate of 2 % and showed phenotypic and genetic traits from both maternal cells. CD163 expression in MCF-7 cells could not be induced by paracrine interaction with M2-activated macrophages. CD163 positive cancer cells in tumor sections grew in clonal collection and a cutoff point >25 % of positive cancer cells was significantly correlated to disease free and overall survival.
  
  
  CONCLUSIONS
  In conclusion, macrophage traits in breast cancer might be caused by cell fusion rather than explained by paracrine cellular interaction. These data provide new insights into the role of cell fusion in breast cancer and contributes to the development of clinical markers to identify cell fusion.
authors.affiliation: Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, SE 581 85, Linköping, Sweden. Ivan.Shabo@ki.se.|Department of Surgery, County Council of Östergötland, Linköping, Sweden. Ivan.Shabo@ki.se.|Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Ivan.Shabo@ki.se.|Department of Breast and Endocrine Surgery, Karolinska University Hospital, SE 171 77, Stockholm, Sweden. Ivan.Shabo@ki.se.
authors.forename: Ivan
authors.initials: I
authors.lastname: Shabo
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, Sweden. krimi000@student.liu.se.
authors.forename: Kristine
authors.initials: K
authors.lastname: Midtbö
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, Sweden. Henrik.A.Andersson@regionostergotland.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Andersson
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, Sweden. emma.akerlund@ki.se.
authors.forename: Emma
authors.initials: E
authors.lastname: Åkerlund
authors.affiliation: Division of Pathology, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, Sweden. hansolsson33@telia.com.
authors.forename: Hans
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, Sweden. Pia.Wegman@regionostergotland.se.
authors.forename: Pia
authors.initials: P
authors.lastname: Wegman
authors.affiliation: Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, Sweden. Cecilia.Gunnarsson@liu.se.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Gunnarsson
authors.affiliation: Division of Cell Biology, Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköping University, Linköping, Sweden. Annelie.linsdtrom@liu.se.
authors.forename: Annelie
authors.initials: A
authors.lastname: Lindström
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002459:Cell Fusion; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000166:cytology*; D019899:Paracrine Communication; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism*; D016019:Survival Analysis; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D011956:Receptors, Cell Surface