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

Groups of CBA mice immunosuppressed with anti-thymocyte serum (ATS) treatme nt were xeno-transplanted with either HeLa human cervical carcinoma cells o r genetically modified cells expressing the human tumor necrosis factor-alp ha (TNF) gene (A11 cells). Both cell lines were highly resistant to the cyt otoxic effects of TNF. If 3X10(6) tumor cells were inoculated s.c. into fem ale mice, HeLa cells grew progressively into large tumors and killed 74% of the recipients, while TNF-expressing A11 cells caused fatal tumor growth o nly in 22% of the mice. 3X10(6) or 1.5X10(7) 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, circula ting TNF reappeared and reached high levels (12-1000 U/ml) 3 to 7 weeks lat er, when the animals bore large tumors (14-23 mm). Generally, such mice bec ame cachectic, severely anemic, hypothermic, and soon died. On account of c alcium mobilization from bones, their serum Ca levels were high. Electron m icroscopy revealed severe liver damage, but there were no signs of chronic arthritis. These results suggest that ATS-treated mice xenotransplanted wit h TNF-gene-transfected A11 human tumor cells provide a new model for studyi ng the pathophysiological and anti-tumor effects of TNF.