Division of Oncology, Department of Clinical and Experimental Medicine, Linköping University, Linköping 58185, Sweden.
J Immunol. 2013 Apr 15;190(8):4420-30. doi: 10.4049/jimmunol.1202610. Epub 2013 Mar 15.
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.
基质金属蛋白酶（MMPs）已被认为是癌症治疗的治疗靶点，但广谱 MMP 抑制剂在临床试验中失败了。最近的数据表明，包括 MMP-9 在内的几种 MMP 既具有促肿瘤发生作用，也具有抗肿瘤发生作用。MMP 的天然抑制剂组织金属蛋白酶抑制剂（TIMPs）也是如此。MMP-9 的抑制剂是 TIMP-1，这种酶的高水平与乳腺癌患者生存率降低有关。炎症是癌症进展的一个标志，MMPs/TIMPs 可能参与局部免疫调节。我们研究了 MMP-9/TIMP-1 在调节乳腺癌固有抗肿瘤免疫中的作用。在裸鼠中建立乳腺癌，并通过瘤内注射携带人 TIMP-1 或 MMP-9 基因的腺病毒（AdMMP-9）进行治疗。进行体内微透析以采样癌细胞衍生（人）和基质衍生（鼠）蛋白、免疫染色以及细胞培养。我们报告了 AdMMP-9 治疗后肿瘤生长和血管生成的剂量依赖性减少。除了增加内皮抑素的产生外，AdMMP-9 通过诱导大量中性粒细胞浸润来促进抗肿瘤免疫反应。在基因转移前耗尽中性粒细胞可消除 AdMMP-9 的治疗效果。此外，AdMMP-9 还在体内和体外将肿瘤浸润的巨噬细胞激活为抑制肿瘤的表型。AdMMP-9 还抑制了携带乳腺癌的免疫功能正常的小鼠的肿瘤生长。携带人 TIMP-1 基因的腺病毒对肿瘤生长或免疫反应没有影响。我们的新数据将 MMP-9 确定为调节固有免疫反应转化为抗肿瘤活性的有力因素。
