Pathophysiological effects of human TNF-alpha-producing tumor xenografts in immunosuppressed mice

Abstract

Groups of CBA mice immunosuppressed with anti-thymocyte serum (ATS) treatment were xenotransplanted with either HeLa human cervical carcinoma cells or genetically modified cells expressing the human tumor necrosis factor-α (TNF) gene (A11 cells). Both cell lines were highly resistant to the cytotoxic effects of TNF. If 3 x 106 tumor cells were inoculated s.c. into female mice, HeLa cells grew progressively into large tumors and killed 74% of the recipients, while TNF-expressing A11 cells caused fatal tumor growth only in 22% of the mice. 3 x 106 or 1.5 x 107 A11 cells produced progressive tumor growth and lethality in all male recipients. In sera of all the A11-cell-transplanted mice, biologically active TNF was detected shortly (4.5 h) after tumor inoculation (6-39 U/ml), decreasing to below detection level in the circulation by day 3. In recipients of 15 million A11 cells, circulating TNF reappeared and reached high levels (12-1000 U/ml) 3 to 7 weeks later, when the animals bore large tumors (14-23 mm). Generally, such mice became cachectic, severely anemic, hypothermic, and soon died. On account of calcium mobilization from bones, their serum Ca levels were high. Electron microscopy revealed severe liver damage, but there were no signs of chronic arthritis. These results suggest that ATS-treated mice xenotransplanted with TNF-gene-transfected A11 human tumor cells provide a new model for studying the pathophysiological and anti-tumor effects of TNF.