Gallo-Hendrikx E, Copps J, Percy D, Croy B A, Wildeman A G
Department of Molecular Biology & Genetics, University of Guelph, Ontario, Canada.
Oncogene. 1994 Oct;9(10):2983-90.
Metastatic pancreatic cancer presents a bleak prognosis. Typically, human tumor development has been modelled in animals by generating transgenic mice carrying an oncogene, and metastasis studied by engrafting human tumor cells into immunodeficient mice. We derived mouse lines that spontaneously develop metastatic pancreatic cancer by crossing a transgenic line that develops primary pancreatic adenocarcinomas with lines that are deficient for different lymphocyte components of the immune system. We obtained transgenics carrying the SCID mutation resulting in loss of B and T cell function, those carrying the beige mutation resulting in impaired NK cell and macrophage activity, and those carrying both mutations. Although human graft studies indicated that the SCID mutation permits metastasis of different types of tumor cells, in our mice its effect on metastasis of the pancreatic tumor was minimal. In contrast, the beige mutation resulted in metastasis in almost 90% of the animals. The SCID and beige mutations synergistically resulted in faster growing tumors. Both primary tumors and metastases contained undifferentiated and differentiated cell types. The tissue distribution of metastases was similar to that recorded from human patients with pancreatic cancer, suggesting that mechanisms underlying metastasis in these mice could be similar to those involved in human disease.
转移性胰腺癌的预后很差。通常，人类肿瘤的发展是通过构建携带癌基因的转基因小鼠在动物体内进行建模的，而转移则是通过将人类肿瘤细胞移植到免疫缺陷小鼠体内进行研究的。我们通过将一个能发生原发性胰腺腺癌的转基因品系与免疫系统不同淋巴细胞成分缺陷的品系杂交，培育出了能自发发生转移性胰腺癌的小鼠品系。我们获得了携带SCID突变导致B细胞和T细胞功能丧失的转基因小鼠、携带米色突变导致NK细胞和巨噬细胞活性受损的转基因小鼠以及同时携带这两种突变的转基因小鼠。尽管人类移植研究表明SCID突变允许不同类型的肿瘤细胞发生转移，但在我们的小鼠中，它对胰腺肿瘤转移的影响很小。相比之下，米色突变导致近90%的动物发生转移。SCID和米色突变协同导致肿瘤生长更快。原发性肿瘤和转移瘤都包含未分化和分化的细胞类型。转移瘤的组织分布与胰腺癌人类患者记录的相似，这表明这些小鼠转移的潜在机制可能与人类疾病中的机制相似。
