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Inflammation Induced by MMP-9 Enhances Tumor Regression of Experimental Breast Cancer

Leifler, Karin Söderlund (författare)
Svensson, Susanne (författare)
Abrahamsson, Annelie (författare)
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Bendrik, Christina (författare)
Robertson, Jennifer (författare)
Gauldie, Jack (författare)
Olsson, Anna-Karin, (författare)
Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, Biochemistry and Molecular Cell Biology; Anna-Karin Olsson
Dabrosin, Charlotta (författare)
Söderlund, Karin, (författare)
Linköpings universitet, Onkologi, Linköpings universitet, Hälsouniversitetet
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Uppsala universitet Medicinska och farmaceutiska vetenskapsområdet. Medicinska fakulteten. Institutionen för medicinsk biokemi och mikrobiologi. (creator_code:org_t)
Linköpings universitet Institutionen för klinisk och experimentell medicin. Onkologi. (creator_code:org_t)
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Linköpings universitet Hälsouniversitetet. (creator_code:org_t)
Östergötlands Läns Landsting Centrum för kirurgi, ortopedi och cancervård. Onkologiska kliniken US. (creator_code:org_t)
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2013
Engelska.
Ingår i: Journal of Immunology. - American Association of Immunologists. - 0022-1767. ; 190:8, s. 4420-4430
  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  (hsv//swe)
MEDICAL AND HEALTH SCIENCES  (hsv//eng)

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MEDICINE
MEDICIN

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