title: Liposome encapsulated zoledronate favours M1-like behaviour in murine macrophages cultured with soluble factors from breast cancer cells.
abstract: BACKGROUND
  Tumour stromal macrophages differentiate to tumour-associated macrophages (TAMs) with characteristics of immunosuppressive M2-type macrophages, having a central role in promoting tumour vascularisation, cancer cell dissemination and in suppressing anti-cancer immune responses. Bisphosphonates (BPs) are a group of drugs commonly used as anti-resorptive agents. Further, nitrogen containing BPs like Zoledronate (ZOL), are known to cause unspecific inflammatory reactions hence the hypothesis that its use could modulate TAMs polarization toward a more inflammatory phenotype.
  
  
  METHODS
  We studied the in vitro polarization of J774 murine macrophages upon culture in 4T1 breast cancer cell-conditioned medium (4T1CM) and stimulation with LPS and free and liposome-encapsulated bisphosphonates.
  
  
  RESULTS
  In this system, breast cancer soluble factors reduced the pro-inflammatory activation of macrophages but increased the secretion of matrix metalloproteinases (MMPs). In the presence of 4T1CM, a non-cytotoxic dose of liposome-encapsulated ZOL (ZOL-LIP) enhanced the expression of iNOS and TNF-α, markers of M1 activation, but did not diminish the expression of M2-type markers. In contrast, clodronate treatment either as a free drug (CLO) or liposome-encapsulated (CLO-LIP) decreased the expression of the M1-type markers and was highly cytotoxic to the macrophages.
  
  
  CONCLUSIONS
  Breast cancer cells soluble factors modulate macrophages toward M2 activation state. Bisphosphonates may be applied to counteract this modulation. We propose that ZOL-LIP may be suitable for favouring cytotoxic immune responses by TAMs in breast cancer, whereas CLO-LIP may be appropriate for TAM depletion.
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. sofia.sousa@uef.fi.
authors.forename: Sofia
authors.initials: S
authors.lastname: Sousa
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. seppo.auriola@uef.fi.
authors.forename: Seppo
authors.initials: S
authors.lastname: Auriola
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. jukka.monkkonen@uef.fi.
authors.forename: Jukka
authors.initials: J
authors.lastname: Mönkkönen
authors.affiliation: School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. jorma.maatta@uef.fi.|Institute of Biomedicine, Department of Cell Biology and Anatomy, University of Turku, Turku, Finland. jorma.maatta@uef.fi.
authors.forename: Jorma
authors.initials: J
authors.lastname: Määttä
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D004164:Diphosphonates / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008081:Liposomes; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000077211:Zoledronic Acid
chemical_list: D017077:Culture Media, Conditioned; D004164:Diphosphonates; D007093:Imidazoles; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D000077211:Zoledronic Acid; D052247:Nitric Oxide Synthase Type II; D020782:Matrix Metalloproteinases