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CD95 signaling deficient mice with a wild-type hematopoietic system are prone to hepatic neoplasia

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Abstract

Patients with mutations in the death receptor CD95 (Fas/APO-1) frequently develop B-cell lymphoma. However, solid tumors have not been found in the context of defective CD95. This could be due to the fatal autoimmune proliferative disease that develops in the absence of functional CD95 or to a difference in CD95 signaling in lymphoid versus nonlymphoid tissues. To test this we reconstituted mice that harbor a point mutation in the death domain of CD95 (lprcg mice), either in one or in both alleles, with bone marrow from wild-type (wt) mice. After a year one third of the lprcg/lprcg mice developed spontaneous hepatic neoplasms. In contrast only one of the wt/lprcg mice and none of the wt mice developed liver cancer. The agonistic anti-CD95 antibody Jo2 induced massive apoptosis in the liver of wt mice but not in the livers of either wt/lprcg or lprcg/lprcg mice. The susceptibility of lprcg/lprcg mice to liver cancer cannot solely be due to impaired CD95 mediated apoptosis because there was no clear correlation between apoptosis resistance and tumor formation. A gene chip analysis identified genes selectively upregulated in the liver of wt and wt/lprcg mice which may protect these mice from developing liver cancer. Our data represent the first case of CD95 protecting from developing a solid cancer.

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Abbreviations

ADA:

Anti-DNA antibodies

BM:

Bone marrow transplantation

Lpr:

Lymphoproliferation

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

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Acknowledgements

We like to thank Terry Lee for performing histology, Xinmin Li for performing the gene array analysis and Nathan Little for help with the AOM/DSS model. We are grateful to Dr. Marisa Alegre for help with the FACS analysis and ELISA used in the study, to Dr. Kazutoshi Sayama for providing the lprcg mice and to Dr. Greg Gores for helpful discussions. The authors have no conflicting financial interests.

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Author notes

  1. Philip G. Ashton-Rickardt

    Present address: Department of Immunology, Division of Medicine, Imperial College London, London, W12 0NN, UK

Authors and Affiliations

  1. Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA

    Sun-Mi Park, Tharinda W. Rajapaksha & Marcus E. Peter

  2. Department of Pathology, The University of Chicago, Chicago, IL, 60637, USA

    Manling Zhang, Husain A. Sattar & Philip G. Ashton-Rickardt

  3. Department of Surgery, The University of Chicago, Chicago, IL, 60637, USA

    Alessandro Fichera

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  1. Sun-Mi Park
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Correspondence to Marcus E. Peter.

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Park, SM., Rajapaksha, T.W., Zhang, M. et al. CD95 signaling deficient mice with a wild-type hematopoietic system are prone to hepatic neoplasia. Apoptosis 13, 41–51 (2008). https://doi.org/10.1007/s10495-007-0149-6

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  • DOI: https://doi.org/10.1007/s10495-007-0149-6

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