ENHANCEMENT OF PANCREATIC TUMOR-METASTASIS IN TRANSGENIC IMMUNODEFICIENT MICE

Metastatic pancreatic cancer presents a bleak prognosis. Typically, hu man tumor development has been modelled in animals by generating trans genic mice carrying an oncogene, and metastasis studied by engrafting human tumor cells into immunodeficient mice. We derived mouse lines th at spontaneously develop metastatic pancreatic cancer by crossing a tr ansgenic line that develops primary pancreatic adenocarcinomas with li nes that are deficient for different lymphocyte components of the immu ne system. We obtained transgenics carrying the SCID mutation resultin g in loss of B and T cell function, those carrying the beige mutation resulting in impaired NK cell and macrophage activity, and those carry ing both mutations. Although human graft studies indicated that the SC ID mutation permits metastasis of different types of tumor cells, in o ur mice its effect on metastasis of the pancreatic tumor was minimal. In contrast, the beige mutation resulted in metastasis in almost 90% o f the animals. The SCID and beige mutations synergistically resulted i n faster growing tumors. Both primary tumors and metastases contained undifferentiated and differentiated cell types. The tissue distributio n 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.