Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo
Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo
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DOI：
10.1158/0008-5472.can-08-0295
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Dabrosin, Charlotta
中科院分区：
文献类型：
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作者：
Bendrik, Christina;Robertson, Jennifer;Dabrosin, Charlotta
基质金属蛋白酶（MMP）通过降解细胞外基质，是血管生成和肿瘤进展的重要调节因子。使用MMP抑制剂的临床试验已经失败，最近的研究表明MMP可以相反地抑制肿瘤生长。然而，目前尚不清楚MMPs或其抑制剂，金属蛋白酶组织抑制剂（TIMP），是否可以用作已建立的癌症的治疗。在这里，携带MMP-9，TIMP-1或空对照的人基因的腺病毒载体被瘤内注射到补充雌二醇并用他莫昔芬治疗的小鼠中建立的乳腺癌中。微透析用于定量MNIP活性，并原位取样内皮抑素和血管内皮生长因子（VEGF）。我们发现AdMMP-9在体内增加MMP活性，降低肿瘤生长速率，并显著减少微血管面积。AdMMP-9治疗导致体内内皮抑制素水平显著增加，而VEGF水平不受影响。如前所述，他莫昔芬暴露本身增加了所有治疗组的MMP活性。此外，与单独治疗相比，AdMMP-9和他莫昔芬的联合治疗进一步降低了肿瘤生长并增加了内皮抑素水平。TIMP-1的基因转移对肿瘤进展没有影响，并抵消了他莫昔芬在我们的乳腺癌模型中的治疗作用。这是第一份报告显示MMP-9的过度表达导致抗血管生成片段的产生增加，血管生成减少，以及对已建立的乳腺癌的治疗效果。【巨蟹座
Matrix metalloproteinases (MMP) are important regulators of angiogenesis and tumor progression by degradation of extracellular matrix. Clinical trials using MMP inhibitors have failed and recent studies suggest that MMPs may in contrast suppress tumor growth. It is not known, however, if MMPs or their inhibitors, tissue inhibitor of metalloproteinases (TIMP), can be used as therapy of established cancer. Here, adenovirus vectors carrying the human genes for MMP-9, TIMP-1, or empty controls were injected intratumorally in breast cancers established in mice supplemented with estradiol and treated with tamoxifen. Microdialysis was used to quantify MNIP activity and sampling of endostatin and vascular endothelial growth factor (VEGF) in situ. We show that AdMMP-9 increased MMP activity in vivo, decreased tumor growth rate, and decreased microvessel area significantly. AdMMP-9 therapy resulted in significantly increased levels of endostatin in vivo, whereas VEGF levels were unaffected. As previously shown, tamoxifen exposure by itself increased MMP activity in all treatment groups. Moreover, the combined therapy with AdMMP-9 and tamoxifen further reduced tumor growth and increased the endostatin levels compared with either treatment alone. Gene transfer of TIMP-1 had no effects on tumor progression and counteracted the therapeutic effect of tamoxifen in our breast cancer model. This is the first report showing that overexpression of MMP-9 results in increased generation of antiangiogenic fragments, decreased angiogenesis, and therapeutic effects of established breast cancer. [Cancer