title: Morphine Modulates Interleukin-4- or Breast Cancer Cell-induced Pro-metastatic Activation of Macrophages.
abstract: Interactions between cancer cells and stromal cells in the tumour microenvironment play a key role in the control of invasiveness, metastasis and angiogenesis. Macrophages display a range of activation states in specific pathological contexts and alternatively activated (M2) macrophages can promote tumour aggressiveness. Opioids are able to modulate tumour growth and metastasis. We tested whether morphine modulates the activation of macrophages induced by (i) interleukin-4 (IL-4), the prototypical M2 polarization-inducing cytokine, or (ii) coculture with breast cancer cells. We showed that IL-4 causes increased MMP-9 production and expression of the alternative activation markers arginase-1 and MRC-1. Morphine prevented IL-4-induced increase in MMP-9 in a naloxone- and methylnaltrexone-reversible fashion. Morphine also prevented IL-4-elicited alternative activation of RAW264.7 macrophages. Expression of MMP-9 and arginase-1 were increased when RAW264.7 were subjected to paracrine activation by 4T1 cells, and this effect was prevented by morphine via an opioid receptor-mediated mechanism. Morphine further decreased 4T1 breast cancer cell invasion elicited by co-culture with RAW264.7. Reduction of MMP-9 expression and alternative activation of macrophages by morphine was confirmed using mouse bone marrow-derived macrophages. Taken together, our results indicate that morphine may modulate tumour aggressiveness by regulating macrophage protease production and M2 polarization within the tumour microenvironment.
authors.affiliation: University of Queensland School of Pharmacy, PACE, 20 Cornwall Street, Woollloongabba QLD 4102, Australia.
authors.forename: Samira
authors.initials: S
authors.lastname: Khabbazi
authors.affiliation: CNRS UPR3212, Institut des Neurosciences Cellulaires et Intégratives, Centre National de la Recherche Scientifique and University of Strasbourg, 5 rue Blaise Pascal, 67084 Strasbourg, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Goumon
authors.affiliation: University of Queensland School of Pharmacy, PACE, 20 Cornwall Street, Woollloongabba QLD 4102, Australia.
authors.forename: Marie-Odile
authors.initials: MO
authors.lastname: Parat
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction
chemical_list: C581013:MRC1 protein, mouse; D008562:Membrane Glycoproteins; D000644:Quaternary Ammonium Compounds; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C032257:methylnaltrexone; D015847:Interleukin-4; D009270:Naloxone; D009271:Naltrexone; D009020:Morphine; D020780:Matrix Metalloproteinase 9; C544448:Arg1 protein, mouse; D001119:Arginase