title: Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancer.
abstract: Matrix metalloproteinases (MMPs) have been suggested as therapeutic targets in cancer treatment, but broad-spectrum MMP inhibitors have failed in clinical trials. Recent data suggest that several MMPs including MMP-9 exert both pro- and antitumorigenic properties. This is also the case of the natural inhibitors of MMPs, tissue inhibitor of metalloproteinases (TIMPs). The inhibitor of MMP-9 is TIMP-1, and high levels of this enzyme have been associated with decreased survival in breast cancer. Inflammation is one hallmark of cancer progression, and MMPs/TIMPs may be involved in the local immune regulation. We investigated the role of MMP-9/TIMP-1 in regulating innate antitumor immunity in breast cancer. Breast cancers were established in nude mice and treated with intratumoral injections of adenoviruses carrying the human TIMP-1 or MMP-9 gene (AdMMP-9). In vivo microdialysis for sampling of cancer cell-derived (human) and stroma-derived (murine) proteins, immunostainings, as well as cell cultures were performed. We report a dose-dependent decrease of tumor growth and angiogenesis after AdMMP-9 treatment. In addition to increased generation of endostatin, AdMMP-9 promoted an antitumor immune response by inducing massive neutrophil infiltration. Neutrophil depletion prior to gene transfer abolished the therapeutic effects of AdMMP-9. Additionally, AdMMP-9 activated tumor-infiltrating macrophages into a tumor-inhibiting phenotype both in vivo and in vitro. AdMMP-9 also inhibited tumor growth in immune-competent mice bearing breast cancers. Adenoviruses carrying the human TIMP-1 gene had no effect on tumor growth or the immune response. Our novel data identify MMP-9 as a potent player in modulating the innate immune response into antitumor activities.
authors.affiliation: Division of Oncology, Department of Clinical and Experimental Medicine, Linköping University, Linköping 58185, Sweden.
authors.forename: Karin Söderlund
authors.initials: KS
authors.lastname: Leifler
authors.forename: Susanne
authors.initials: S
authors.lastname: Svensson
authors.forename: Annelie
authors.initials: A
authors.lastname: Abrahamsson
authors.forename: Christina
authors.initials: C
authors.lastname: Bendrik
authors.forename: Jennifer
authors.initials: J
authors.lastname: Robertson
authors.forename: Jack
authors.initials: J
authors.lastname: Gauldie
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Olsson
authors.forename: Charlotta
authors.initials: C
authors.lastname: Dabrosin
mesh_terms: D000230:Adenocarcinoma; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000276:immunology* / Q000628:therapy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D061986:MCF-7 Cells; D008262:Macrophage Activation / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020556:Neutrophil Infiltration / Q000276:immunology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9