DNA repair-deficient Xpa/p53 knockout mice are sensitive to the non-genotoxic carcinogen cyclosporine A: escape of initiated cells from immunosurveillance?
The DNA repair-deficient Xpa(-/-)p53(+/-) (Xpa/p53) mouse is a potent model for carcinogenicity testing, representing increased sensitivity toward genotoxic but surprisingly also toward true human non-genotoxic carcinogens. The mechanism of this increased sensitivity in Xpa/p53 mice toward non-genotoxic carcinogens is still unknown. Here, we investigated the mechanism of the human non-genotoxic carcinogen cyclosporine A (CsA) in the Xpa/p53 mouse model. Xpa/p53 mice exposed to CsA for 39 weeks showed a significantly increased lymphoma incidence as compared with untreated Xpa/p53 mice and CsA-treated wild-type (WT) mice. We excluded concealed genotoxicity of CsA in Xpa/p53 mice by mutant frequency analyses. As a next step, we used a genetic approach: immunodeficient DNA-PKcs mice, defective in the catalytic subunit of the DNA-dependent protein kinase, were crossed with Xpa and Xpa/p53 mice. Xpa/p53 mice had an increased lymphoma incidence with shorter latency times as compared with DNA-PKcs-deficient WT and Xpa mice. Surprisingly, also six of 15 DNA-PKcs/Xpa/p53 females had developed an adenocarcinoma of the mammary gland. Tumor responses in CsA-treated and DNA-PKcs-deficient Xpa/p53 mice were comparable as both genotypes developed mainly splenic lymphomas enriched in B lymphocytes. From our present studies, we hypothesize that levels of initiated precancerous cells are elevated in Xpa/p53 mice. These cells are insufficiently eliminated due to either suppression of the immune system by CsA or through immune-related DNA-PKcs deficiency. Based on the current studies and those conducted previously, we conclude that the Xpa/p53 model is an excellent adjunct to the current chronic rodent bioassay.
van Kesteren
Petra C E
PC
Laboratory for Health Protection Research, National Institute of Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Beems
Rudolf B
RB
Luijten
Mirjam
M
Robinson
Joke
J
de Vries
Annemieke
A
van Steeg
Harry
H
D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D000818:Animals; D001681:Biological Assay; D002273:Carcinogens / Q000633:toxicity*; D016572:Cyclosporine / Q000633:toxicity*; D004249:DNA Damage; D005260:Female; D008223:Lymphoma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009152:Mutagenicity Tests; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D016572:Cyclosporine