title: M2-like macrophages induce colon cancer cell invasion via matrix metalloproteinases.
abstract: The inflammatory milieu plays an important role in colon cancer development and progression. Previously, we have shown that tumor-associated macrophages (TAMs), an important component of the tumor microenvironment, are enriched in tumors compared with normal tissue and confer a poorer prognosis. In the present study, we found that matrix metallopeptidase-9 (MMP-9), which degrades extracellular matrix proteins, was increased in biopsies from colon cancer patients and in mouse xenografts with SW480 cell-derived tumors. SW480 colon cancer cells exposed to M2-like macrophage-conditioned medium (M2-medium) exhibited increased MMP-9 mRNA, protein expression and gelatinase activity. A similar effect was obtained by the addition of tumor necrosis factor-α (TNFα) and leukotriene D4(LTD4). MMP-9 expression and activity were reduced by a TNFα blocking antibody adalimumab and a cysteinyl leukotriene receptor 1 (CysLTR1, the receptor for LTD4) antagonist montelukast. M2-medium also induced changes in the epithelial-mesenchymal transition (EMT) markers E-cadherin, β-catenin, vimentin, and snail in SW480 cells. We also found that both M2-medium and TNFα and LTD4induced stabilization/nuclear translocation of β-catenin. Furthermore, we also observed an elongated phenotype that may indicate increased invasiveness, as confirmed in a collagen I invasion assay. M2-medium increased the invasive ability, and a similar effect was also obtained by the addition of TNFα and LTD4. The specific MMP inhibitor I or adalimumab and montelukast reduced the number of invasive cells. In conclusion, our findings show that M2-medium enriched in TNFα and LTD4promote colon cancer cell invasion via MMP-9 expression and activation and the induction of EMT.
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Katyayni
authors.initials: K
authors.lastname: Vinnakota
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Benson Chellakkan
authors.initials: BC
authors.lastname: Selvanesan
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Geriolda
authors.initials: G
authors.lastname: Topi
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Tavga
authors.initials: T
authors.lastname: Salim
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Janna
authors.initials: J
authors.lastname: Sand-Dejmek
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: Division of Cell and Experimental Pathology, Department of Translational Medicine, Clinical Research Centre, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: Anita
authors.initials: A
authors.lastname: Sjölander
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017998:Leukotriene D4 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017077:Culture Media, Conditioned; D020024:Leukotriene Antagonists; D061965:Matrix Metalloproteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D017998:Leukotriene D4; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
keywords: LTD4; M2 macrophages; MMPs; TNFα; colon cancer; epithelial-mesenchymal transition; tumor cell invasion; tumor-associated macrophages