Polyoma virus-induced osteosarcomas in inbred strains of mice: host determinants of metastasis.
Polyoma virus-induced osteosarcomas in inbred strains of mice: host determinants of metastasis.
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DOI：
10.1371/journal.ppat.1000733
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发表时间：
2010-01-22
期刊：
影响因子：
6.7
通讯作者：
Benjamin T
中科院分区：
文献类型：
--
作者：
Velupillai P;Sung CK;Tian Y;Dahl J;Carroll J;Bronson R;Benjamin T
小鼠多瘤病毒在许多近交系小鼠中诱导广泛的实体瘤。在大多数菌株中，肿瘤生长迅速，但不能转移。在Czech-II/Ei小鼠中发现了一个例外，其中骨肿瘤定期转移到肺。这些肿瘤在肺转移的倾向上类似于人骨肉瘤。从这些转移性肿瘤建立的细胞系已与C3 H/BiDa小鼠中产生的非转移性骨肉瘤的细胞系进行了比较。骨桥蛋白是一种参与迁移和转移的趋化因子，已知其由病毒中T抗原转录诱导。Czech-II/Ei和C3 H/BiDa肿瘤细胞表达中T，并分泌骨桥蛋白，其水平与主要化学引诱物相当。肿瘤细胞系迁移同样好地响应重组骨桥蛋白作为唯一的引诱剂。一个重要的差异出现在入侵的测定中，其中来自Czech-II/Ei小鼠的肿瘤细胞能够入侵穿过细胞外基质屏障，而来自C3 H/BiDa小鼠的肿瘤细胞不能入侵。侵袭行为与金属蛋白酶MMP-2和转录因子NFAT水平升高有关。抑制MMP-2或NFAT可抑制Czech-II/Ei骨肉瘤细胞的侵袭。转移表型在F1小鼠中占主导地位。来自F1小鼠的骨肉瘤细胞系表达中等水平的MMP-2和NFAT，并且具有侵袭性。Czech-II/Ei小鼠的骨肉瘤保留了功能性p53。这种转移的病毒宿主模型不同于靶向p53或pRb的工程模型，并提供了一个系统，用于研究在没有p53丢失的情况下骨肿瘤转移的遗传和分子基础。致癌小鼠多瘤病毒及其突变体以前已被用于研究使用标准近交系小鼠品系作为共同宿主的肿瘤诱导的病毒决定因素。在这里，我们使用野生型病毒来研究宿主遗传背景的作用，重点是两种不同的宿主株骨肿瘤转移。比较这些小鼠的骨肉瘤细胞系，我们已经确定了一个分子途径，该途径是体外侵袭行为的基础，并与体内转移相关。该途径涉及在作为转录调节因子的NFAT的部分控制下分泌金属蛋白酶MMP-2。这种病毒-宿主系统反映了人骨肉瘤肺转移的一个重要特征。基于近交系小鼠之间天然存在的差异，该模型不同于靶向p53或pRb作为人类疾病中已知风险因素的基因工程模型。转移性骨肉瘤保留了功能性p53。正如其他人所指出的，局部与转移性疾病患者中p53丢失的频率是相同的，这表明p53丢失以外的事件在转移中很重要。虽然基因工程模型中转移的下游效应物仍然未知，但本文提供的证据表明NFAT → MMP-2通路在转移性骨肉瘤的发展中上调。
The mouse polyoma virus induces a broad array of solid tumors in mice of many inbred strains. In most strains tumors grow rapidly but fail to metastasize. An exception has been found in the Czech-II/Ei mouse in which bone tumors metastasize regularly to the lung. These tumors resemble human osteosarcoma in their propensity for pulmonary metastasis. Cell lines established from these metastatic tumors have been compared with ones from non-metastatic osteosarcomas arising in C3H/BiDa mice. Osteopontin, a chemokine implicated in migration and metastasis, is known to be transcriptionally induced by the viral middle T antigen. Czech-II/Ei and C3H/BiDa tumor cells expressed middle T and secreted osteopontin at comparable levels as the major chemoattractant. The tumor cell lines migrated equally well in response to recombinant osteopontin as the sole attractant. An important difference emerged in assays for invasion in which tumor cells from Czech-II/Ei mice were able to invade across an extracellular matrix barrier while those from C3H/BiDa mice were unable to invade. Invasive behavior was linked to elevated levels of the metalloproteinase MMP-2 and of the transcription factor NFAT. Inhibition of either MMP-2 or NFAT inhibited invasion by Czech-II/Ei osteosarcoma cells. The metastatic phenotype is dominant in F1 mice. Osteosarcoma cell lines from F1 mice expressed intermediate levels of MMP-2 and NFAT and were invasive. Osteosarcomas in Czech-II/Ei mice retain functional p53. This virus-host model of metastasis differs from engineered models targeting p53 or pRb and provides a system for investigating the genetic and molecular basis of bone tumor metastasis in the absence of p53 loss. The oncogenic mouse polyoma virus and its mutants have previously been used to investigate viral determinants of tumor induction using a standard inbred mouse strain as a common host. Here we use wild type virus to investigate the role of the host genetic background, focusing on two host strains that differ with respect to bone tumor metastasis. Comparing osteosarcoma cell lines from these mice, we have identified a molecular pathway that underlies invasive behavior in vitro and correlates with metastasis in vivo. The pathway involves secretion of the metalloproteinase MMP-2 under partial control of NFAT as a transcriptional regulator. This virus-host system reflects an important feature of human osteosarcoma with respect to pulmonary metastasis. Based on naturally occurring differences among inbred mice, the model differs from genetically engineered models targeting p53 or pRb as known risk factors in the human disease. Here, metastatic osteosarcomas retain functional p53. As noted by others, the frequency of p53 loss in patients with localized versus metastatic disease is the same, suggesting that events beyond p53 loss are important in metastasis. While the downstream effectors of metastasis in the genetically engineered models remain unknown, evidence presented here implicates upregulation of an NFAT → MMP-2 pathway in the development of metastatic osteosarcoma.
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影响因子：
15.3
作者：
LUKACHER, AE;MA, YP;BENJAMIN, TL
通讯作者：
BENJAMIN, TL
DOI：
10.1073/pnas.0805462105
发表时间：
2008-08-19
影响因子：
11.1
作者：
Berman, Seth D.;Calo, Eliezer;Lees, Jacqueline A.
通讯作者：
Lees, Jacqueline A.
影响因子：
4.1
作者：
Alfonso-Jaume, MA;Mahimkar, R;Lovett, DH
通讯作者：
Lovett, DH
影响因子：
5.3
作者：
GUY, CT;CARDIFF, RD;MULLER, WJ
通讯作者：
MULLER, WJ
影响因子：
5.4
作者：
Dahl, J;You, J;Benjamin, TL
通讯作者：
Benjamin, TL