FasL Deficiency Enhances the Development of Tumors in p53+/- Mice

Abstract

In the multistep process of tumor development, several events occur to transform cells from normal to malignant. Although p53 is one of the most commonly mutated genes in a wide variety of tumors, how other genes interact with p53 to transform cells is only just beginning to be understood. To study the effects of the interaction of the Fas system with p53 in tumor progression and development, mice with a targeted disruption of the p53 tumor supressor gene and a mutation in Fas ligand were bred. Organ weights, life expectancy, and tumor and tissue histology were assessed. Although spleen weights were drastically increased in FasL^-/- p53^- ^/- mice, the FasL deficiency had no effect on life expectancy or the tumor spectrum of homozygous p53-deficient mice. The FasL deficiency reduced the median time to death from 12.1 months in FasL^+/+ p53⁺ ^/- mice to 9.6 months in FasL^-/- p53⁺ ^/- mice, and led to a shift in tumor spectrum from predominantly sarcomas (63%) when FasL was present to a large number of lymphomas (76%) in FasL^-/- p53⁺ ^/- mice. Given the reduced life span and increased incidence of lymphoma in FasL^-/- p53⁺ ^/- mice, these mice could be useful in carcinogenicity testing, particularly for understanding mechanisms of compounds that are nongenotoxic.

Keywords

Tumor apoptosis p53 Fas lymphoma sarcoma gld.

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