Loss of collagenase-2 confers increased skin tumor susceptibility to male mice
Loss of collagenase-2 confers increased skin tumor susceptibility to male mice
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DOI：
10.1038/ng1249
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发表时间：
2003-11-01
期刊：
影响因子：
30.8
通讯作者：
López-Otín, C
中科院分区：
文献类型：
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作者：
Balbín, M;Fueyo, A;López-Otín, C
基质金属蛋白酶(MMPs)在肿瘤进展中起着重要作用(1，2)，但大多数使用基质金属蛋白酶抑制剂的临床试验并未显示出对癌症患者的改善(3)。这可能部分是因为大范围的抑制剂也会降低单个MMPs的宿主保护性抗肿瘤特性。我们产生了胶原酶-2(MMP8)缺陷小鼠，这是一种主要由炎症反应中的中性粒细胞产生的胶原酶-2，在一些恶性肿瘤中可检测到(1，4)。Mmp8的缺失不会在胚胎发育期间或成年小鼠中造成异常。然而，与之前对基质金属蛋白酶缺陷小鼠的研究相反，缺乏Mmp8会显著增加男性Mmp8/小鼠皮肤肿瘤的发生率。与野生型小鼠相比，卵巢被摘除或接受他莫昔芬治疗的雌性Mmp8小鼠也更容易患上肿瘤。骨髓移植实验证实，中性粒细胞提供的MMP8足以恢复该酶介导的对雄性小鼠肿瘤发展的自然保护作用。组织病理学分析显示，突变小鼠在致癌物诱导的炎症反应中存在异常。我们的研究确定了Mmp8在癌症中矛盾的保护作用，并提供了一个遗传模型来评估癌症易感性的性别差异的分子基础。
Matrix metalloproteinases (MMPs) have fundamental roles in tumor progression(1,2), but most clinical trials with MMP inhibitors have not shown improvements in individuals with cancer(3). This may be partly because broad-range inhibitors also reduce host-protective antitumor properties of individual MMPs. We generated mice deficient in collagenase-2 (Mmp8), an MMP mainly produced by neutrophils in inflammatory reactions and detected in some malignant tumors(1,4). Loss of Mmp8 did not cause abnormalities during embryonic development or in adult mice. Contrary to previous studies with MMP-deficient mice, however, the absence of Mmp8 strongly increased the incidence of skin tumors in male Mmp8 / mice. Female Mmp8 / mice whose ovaries were removed or were treated with tamoxifen were also more susceptible to tumors compared with wild-type mice. Bone marrow transplantation experiments confirmed that Mmp8 supplied by neutrophils was sufficient to restore the natural protection against tumor development mediated by this protease in male mice. Histopathological analysis showed that mutant mice had abnormalities in the inflammatory response induced by carcinogens. Our study identifies a paradoxical protective role for Mmp8 in cancer and provides a genetic model to evaluate the molecular basis of gender differences in cancer susceptibility.