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.

Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils

“…Massive infiltration of neutrophils may elicit a direct cytotoxic effect by releasing hydrogen peroxide, leading to tumor regression, whereas a low-grade neutrophil gradient is tumor progressive (38,39). This is in line with our present data showing that addition of a high number of neutrophils caused a disintegration of mammospheres in vitro.…”

“…Neutrophils possess dual roles in cancer progression depending on their phenotype or number in the tumor microenvironment (38,39). Massive infiltration of neutrophils may elicit a direct cytotoxic effect by releasing hydrogen peroxide, leading to tumor regression, whereas a low-grade neutrophil gradient is tumor progressive (38,39).…”

Tumor angiogenesis: MMP-mediated induction of intravasation- and metastasis-sustaining neovasculature

“…Similar dependence of infiltrating macrophages on MMP-9 and its proteolytic activity is manifested in plasminogen-knockout mice, where supplementation of active MMP-9 was shown to restore impaired macrophage influx (Gong et al, 2008). In support of the notion that intratumoral MMP-9 can locally regulate influx and presentation of leukocytes in developing tumors, it was demonstrated that the adenovirus-mediated induction of MMP-9 in breast cancer xenografts dramatically altered their cytokine profile and enhanced production of neutrophil chemoattractants, KC and MIP-2, leading to a massive neutrophil infiltration (Leifler et al, 2013). …”

Antioxidant and anti-inflammatory properties of Chinese ilicifolius vegetable (Acanthopanax trifoliatus (L) Merr) and its reference compounds

“…Inflammation is a hallmark of cancer. An MMP-9/TIMP-1 imbalance is also observed in cancers (33). The balance between MMP-9 expression and TIMP-1 expression may be an important indicator of tumor progression and may be useful as a predictor of tumor recurrence (34).…”