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Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
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2013 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 190, no 8, 4420-4430 p.Article in journal (Refereed) Published
Abstract [en]

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. The Journal of Immunology, 2013, 190: 4420-4430.

Place, publisher, year, edition, pages
American Association of Immunologists , 2013. Vol. 190, no 8, 4420-4430 p.
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Medical and Health Sciences
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URN: urn:nbn:se:liu:diva-92700DOI: 10.4049/jimmunol.1202610ISI: 000317274500059OAI: oai:DiVA.org:liu-92700DiVA: diva2:621666
Note

Funding Agencies|Swedish Cancer Society|2009/799|Swedish Research Council|2010-3458|Research Funds of Linkoping University Hospital||

Available from: 2013-05-16 Created: 2013-05-16 Last updated: 2017-12-06Bibliographically approved

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Söderlund, KarinSvensson, SusanneAbrahamsson, AnnelieBendrik, ChristinaDabrosin, Charlotta

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Söderlund, KarinSvensson, SusanneAbrahamsson, AnnelieBendrik, ChristinaDabrosin, Charlotta
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