Szabova L, Chrysovergis K, Yamada S S, Holmbeck K
Matrix Metalloproteinase Unit, Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892-4380, USA.
Oncogene. 2008 May 22;27(23):3274-81. doi: 10.1038/sj.onc.1210982. Epub 2007 Dec 10.
Membrane-type I matrix metalloproteinase (MT1-MMP) is associated with multiple forms of cancer including mammary cancer. To directly evaluate the significance of MT1-MMP expression in tumor progression and metastasis using a genetically induced cancer model, we crossed MT1-MMP-deficient mice to MMTV-polyoma virus middle T-antigen (PyMT) mice. Expression of PyMT in the MT1-MMP-deficient background consistently resulted in hyperplasia of the mammary gland as seen in wild-type PyMT littermates. Following orthotopic transplantation of PyMT+ glands into the cleared mammary fat pad of syngeneic recipient mice, MT1-MMP-deficient tumors were palpable earlier than wild-type tumors. Moreover, MT1-MMP-deficient tumors grew to the experimental end point size quicker than control tumors, but demonstrated markedly reduced ability to metastasize to the lungs of recipient mice. Accordingly, MT1-MMP-deficient mice displayed an overall reduction in metastasis count of 50%. MT1-MMP was expressed solely in the stroma of PyMT-induced tumors and those metastatic nodules that formed in the lungs were devoid of MT1-MMP expression. Stromal fibroblasts isolated from MT1-MMP-deficient tumors did not degrade type I collagen suggesting that efficient dissemination of tumor cells is dependent on stromal cell remodeling of the tumor environment. The data demonstrate directly that MT1-MMP-mediated proteolysis by stromal cells is important in the metastatic process.
膜型基质金属蛋白酶-1（MT1-MMP）与包括乳腺癌在内的多种癌症相关。为了使用基因诱导癌症模型直接评估MT1-MMP表达在肿瘤进展和转移中的意义，我们将MT1-MMP缺陷小鼠与MMTV-多瘤病毒中T抗原（PyMT）小鼠杂交。在MT1-MMP缺陷背景下PyMT的表达持续导致乳腺增生，如同在野生型PyMT同窝小鼠中所见。将PyMT+腺体原位移植到同基因受体小鼠清除的乳腺脂肪垫后，MT1-MMP缺陷肿瘤比野生型肿瘤更早可触及。此外，MT1-MMP缺陷肿瘤比对照肿瘤更快生长到实验终点大小，但转移到受体小鼠肺部的能力明显降低。因此，MT1-MMP缺陷小鼠的转移计数总体降低了50%。MT1-MMP仅在PyMT诱导肿瘤的基质中表达，并且在肺部形成的那些转移结节中没有MT1-MMP表达。从MT1-MMP缺陷肿瘤中分离的基质成纤维细胞不能降解I型胶原，这表明肿瘤细胞的有效播散依赖于肿瘤环境的基质细胞重塑。数据直接表明基质细胞介导的MT1-MMP蛋白水解在转移过程中很重要。
