Matrix metalloproteinases play an active role in Wnt1-induced mammary tumorigenesis
Matrix metalloproteinases play an active role in Wnt1-induced mammary tumorigenesis
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DOI：
10.1158/0008-5472.can-05-2919
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发表时间：
2006-03-01
期刊：
影响因子：
11.2
通讯作者：
DeClerck, YA
中科院分区：
文献类型：
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作者：
Blavier, L;Lazaryev, A;DeClerck, YA
Wnt信号转导通路在几种小鼠和人上皮癌的发病机制中起关键作用。在这里，我们使用小鼠乳腺肿瘤病毒（MMTV）-Wnt 1转基因小鼠，自发性乳腺癌，检查是否基质金属蛋白酶（MMPs）-一个家族的胞外蛋白酶参与癌症进展的多个步骤，促成Wnt 1诱导的肿瘤发生。通过RT-PCR和原位杂交分析几种MMPs的表达，发现MMP-2、MMP-3、MMP-9、MMP-13和MT 1-MMP（MMP-14）在MMTV-Wnt 1转基因小鼠的增生腺体和乳腺肿瘤中的表达增加。有趣的是，尽管MMP-2、MMP-3和MMP-9仅由乳腺肿瘤中的基质细胞表达，但MMP-13和MT 1-MMP除了由肿瘤基质表达外，还由转化的上皮细胞表达。为了确定这些MMPs是否有助于肿瘤发生，将MMTV-Wnt 1小鼠与乳腺中过表达金属蛋白酶组织抑制剂2（一种天然NIMP合成物）的转基因小鼠杂交。在双MMTV-Wnt 1/金属蛋白酶组织抑制剂-2转基因小鼠中，我们观察到肿瘤潜伏期增加，肿瘤形成减少26.3%。此外，与来自TIMITAI-Wntl小鼠的肿瘤相比，这些肿瘤以较慢的速率生长，表现出与血管生成缺陷相关的肿瘤细胞的增殖速率降低18%和凋亡速率增加12.2%。因此，该数据首次为MMPs在Wnt 1诱导的乳腺肿瘤发生中的积极作用提供了证据。
The Wnt signaling transduction pathway plays a critical role in the pathogenesis of several murine and human epithelial cancers. Here, we have used mouse mammary tumor virus (MMTV)-Wnt1 transgenic mice, which develop spontaneous mammary adenocarcinoma, to examine whether matrix metalloproteinases (MMPs)-a family of extracellular proteases implicated in multiple steps of cancer progression-contributed to Wnt1-induced tumorigenesis. An analysis of the expression of several MMPs by RT-PCR and in situ hybridization revealed an increase in the expression of MMP-2, MMP-3, MMP-9, MMP-13, and MT1-MMP (MMP-14) in hyperplastic glands and in mammary tumors of MMTV-Wnt1 trans,genic mice. Interestingly, whereas MMP-2, MMP-3, and MMP-9 were exclusively expressed by stromal cells in mammary tumors, MMP-13 and MT1-MMP were expressed by transformed epithelial cells in addition to the tumor stroma. To determine whether these MMPs contributed to tumorigenesis, MMTV-Wnt1 mice were crossed with transgenic mice overexpressing tissue inhibitor of metalloproteinase-2-a natural NIMP inhibitor-in the mammary gland. In the double MMTV-Wnt1 /tissue inhibitor of metalloproteinases-2 transgenic mice, we observed an increase in tumor latency and a 26.3% reduction in tumor formation. Furthermore, these tumors grew at a slower rate, exhibited an 18% decrease in proliferative rate, and a 12.2% increase in apoptotic rate of the tumor cells in association with a deficit in angiogenesis when compared with tumors from TIMITAI-Wntl mice. Thus, for the first time, the data provides evidence for the active role of MMPs in Wnt1-induced mammary tumorigenesis.