Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10
Tumor cell-derived Timp-1 is necessary for maintaining metastasis-promoting Met-signaling via inhibition of Adam-10
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DOI：
10.1007/s10585-011-9410-z
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发表时间：
2011-12-01
影响因子：
4
通讯作者：
Krueger, Achim
中科院分区：
文献类型：
--
作者：
Schelter, Florian;Grandl, Martina;Krueger, Achim
在许多不同的肿瘤实体中，金属蛋白酶组织抑制剂-1（Timp-1）的表达增加与预后不良相关。我们先前在小鼠模型中报道，Timp-1的全身水平升高诱导肝脏微环境中的基因表达特征，增加该器官对肿瘤细胞的易感性。这种宿主效应依赖于肝细胞生长因子（Hgf）/肝细胞生长因子受体（Met）信号通路活性的增加。在最近的一项研究中，我们发现Met信号传导受Timp-1的调节，因为它抑制Met脱落酶A去整合素和金属蛋白酶-10（Adam-10）。本研究的目的是阐明肿瘤细胞的转移潜力是否也受益于自分泌Timp-1，并涉及Adam-10和Met信号传导。在实验性肝转移的同基因鼠模型中，Timp-1表达和Met信号传导定位于转移集落内并由肿瘤细胞表达。肿瘤细胞Timp-1的敲低抑制了转移中的Met信号传导，并抑制了肝中的转移形成和肿瘤细胞分散。在体外，敲低肿瘤细胞Timp-1阻止了HGF诱导的Met磷酸化。因此，Met脱落酶Adam-10的敲低触发了自身磷酸化和对Hgf的响应。因此，Adam-10敲低增加转移灶中的Met磷酸化并诱导肿瘤细胞分散到周围肝实质中。总之，这些发现表明肿瘤细胞来源的Timp-1作为转移潜能的正调节剂，并支持蛋白酶及其天然抑制剂作为蛋白酶网络的成员是正常稳态和疾病期间信号传导的主要参与者的概念。
In many different tumor entities, increased expression of tissue inhibitor of metalloproteinases-1 (Timp-1) is associated with poor prognosis. We previously reported in mouse models that elevated systemic levels of Timp-1 induce a gene expression signature in the liver microenvironment increasing the susceptibility of this organ to tumor cells. This host effect was dependent on increased activity of the hepatocyte growth factor (Hgf)/hepatocyte growth factor receptor (Met) signaling pathway. In a recent study we showed that Met signaling is regulated by Timp-1 as it inhibits the Met sheddase A disintegrin and metalloproteinase-10 (Adam-10). The aim of the present study was to elucidate whether the metastatic potential of tumor cells benefits from autocrine Timp-1 as well and involves Adam-10 and Met signaling. In a syngeneic murine model of experimental liver metastasis Timp-1 expression and Met signaling were localized within metastatic colonies and expressed by tumor cells. Knock down of tumor cell Timp-1 suppressed Met signaling in metastases and inhibited metastasis formation and tumor cell-scattering in the liver. In vitro, knock down of tumor cell Timp-1 prevented Hgf-induced Met phosphorylation. Consequently, knock down of Met sheddase Adam-10 triggered auto-phosphorylation and responsiveness to Hgf. Accordingly, Adam-10 knock down increased Met phosphorylation in metastatic foci and induced tumor cell scattering into the surrounding liver parenchyma. In conclusion, these findings show that tumor cell-derived Timp-1 acts as a positive regulator of the metastatic potential and support the concept that proteases and their natural inhibitors, as members of the protease web, are major players of signaling during normal homeostasis and disease.