Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis
Matrilysin [MMP-7] expression selects for cells with reduced sensitivity to apoptosis
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DOI：
10.1038/sj.neo.7900190
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发表时间：
2001-11-01
期刊：
影响因子：
4.8
通讯作者：
Matrisian, LM
中科院分区：
文献类型：
--
作者：
Fingleton, B;Vargo-Gogola, T;Matrisian, LM
基质金属蛋白酶基质溶解素（MMP-7）已被证明有助于肿瘤的发展。我们以前已经表明，肿瘤坏死因子家族的成员诱导蛋白是这种酶的底物，导致增加死亡途径信号。本研究的目的是调和matrilysin的促凋亡和促肿瘤功能。在代表肿瘤进展早期阶段并表达Fas配体及其受体的人HBL 100和鼠NMuMG细胞系中，暴露于基质溶解素导致细胞死亡，其可被FasL中和抗体阻断。这些细胞系中基质溶解素的组成型表达选择对Fas介导的细胞凋亡具有降低的敏感性的细胞，如用受体活化抗体和用体外活化的脾细胞所证明的。表达基质溶素的细胞对细胞凋亡的化学诱导剂的敏感性也显著降低。我们提出，在各种肿瘤类型的早期阶段已经报道的基质溶解素的表达可以起到选择细胞的作用，由于免疫监视，去除的机会显著降低。因此，这些细胞更有可能获得额外的遗传修饰并进一步发展为肿瘤。
The matrix metalloproteinase matrilysin (MMP-7) has been demonstrated to contribute to tumor development. We have shown previously that members of the TNF family of apoptosis-inducing proteins are substrates for this enzyme, resulting in increased death pathway signaling. The goal of the current study was to reconcile the proapoptotic and tumor-promoting functions of matrilysin. In the human HBL100 and murine NMuMG cell lines that represent early stages of tumor progression and that express both Fas ligand and its receptor, exposure to matrilysin results in cell death that can be blocked by FasL neutralizing antibodies. Constitutive expression of matrilysin in these cell lines selects for cells with reduced sensitivity to Fas-mediated apoptosis as demonstrated both with a receptor-activating antibody and with in vitro activated splenocytes. Matrilysin-expressing cells are also significantly less sensitive to chemical inducers of apoptosis. We propose that the expression of matrilysin that has been reported at early stages in various tumor types can act to select cells with a significantly decreased chance of removal due to immune surveillance. As a result, these cells are more likely to acquire additional genetic modifications and develop further as tumors.