Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Pathog. 2010 Jan 22;6(1):e1000733. doi: 10.1371/journal.ppat.1000733.
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.
小鼠多瘤病毒能诱导多种近交系小鼠产生广泛的实体肿瘤。在大多数品系中，肿瘤生长迅速，但不会转移。在捷克 II/Ei 小鼠中发现了一个例外，其骨肿瘤经常转移到肺部。这些肿瘤在向肺部转移的倾向方面与人类骨肉瘤相似。从这些转移性肿瘤中建立的细胞系已与源自 C3H/BiDa 小鼠的非转移性骨肉瘤细胞系进行了比较。趋化因子骨桥蛋白（osteopontin）已知可被病毒的中间 T 抗原转录诱导，与迁移和转移有关。捷克 II/Ei 和 C3H/BiDa 肿瘤细胞表达中间 T，并以与主要趋化因子相当的水平分泌骨桥蛋白。肿瘤细胞系在响应重组骨桥蛋白作为唯一趋化物时同样良好地迁移。在侵袭测定中出现了一个重要差异，其中捷克 II/Ei 小鼠的肿瘤细胞能够穿过细胞外基质屏障进行侵袭，而 C3H/BiDa 小鼠的肿瘤细胞则不能。侵袭行为与金属蛋白酶 MMP-2 和转录因子 NFAT 的水平升高有关。MMP-2 或 NFAT 的抑制均抑制捷克 II/Ei 骨肉瘤细胞的侵袭。在 F1 小鼠中，转移表型占优势。F1 小鼠的骨肉瘤细胞系表达中间水平的 MMP-2 和 NFAT，具有侵袭性。捷克 II/Ei 小鼠的骨肉瘤保留功能性 p53。这种针对转移的病毒-宿主模型与针对 p53 或 pRb 的工程模型不同，为在没有 p53 缺失的情况下研究骨肿瘤转移的遗传和分子基础提供了一个系统。
