Transponder-Induced Sarcoma in the Heterozygous p53+/- Mouse

Abstract

Heterozygous p53^+/- transgenic mice are being studied for utility as a short-term alternative model to the 2-yr rodent carcinogenicity bioassay. During a 26-wk study to assess the potential carcinogenicity of oxymetholone using p-cresidine as a positive control, glass/ polypropylene microchips (radio transponder identification devices) were subcutaneously implanted into male and female p53^+/- mice. During week 15, the first palpable mass was clinically observed at an implant site. This rapidly growing mass virtually quadrupled in size by week 25. Microscopic examination of all implant sites revealed that 18 of 177 animals had a subcutaneous histologically malignant sarcoma. The neoplasms were characterized as undifferentiated sarcomas unrelated to drug treatment, as indicated by the relatively even distribution among dose groups, including controls. An unusual preneoplastic mesenchymal change characterized by the term "mesenchymal dysplasia" was present in most groups and was considered to be a prodromal change to sarcoma development. The tumors were observed to arise from dysplastic mesenchymal tissue that developed within the tissue capsule surrounding the transponder. The preneoplastic changes, including mesenchymal dysplasia, appeared to arise at the transponder's plastic anchoring barb and then progressed as a neoplasm to eventually surround the entire microchip. Capsule membrane endothelialization, inflammation, mesenchymal basophilia and dysplasia, and sarcoma were considered unequivocal preneoplastic/neoplastic responses to the transponder and were not related to treatment with either oxymetholone or p-cresidine.

Keywords

Transgenic mice p53+/- mice subcutaneous sarcoma radio transmitter solid state carcinogenesis carcinogenesis models

References

Ball, DJ , Argentieri G. , Krause R. , Lipinski M. , Robison RL , Stoll RE , and Visscher GE (1991). Evaluation of a microchip implant system used for animal identification in rats. Lab Anim. Sci. 41: 185-186.

Brand KG , Buoen LC , Johnson KH , and Brand I. (1975). Etiological factors, stages, and the role of the foreign body in foreign body tumorigenesis: A review. Cancer Res. 35: 279-286.

Donehower LA , Harvey M. , Slagle BL , McArthur MJ , Montgomery Caj , Butel JS , and Bradley A. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356: 215-221.

Harvey M. , McArthur MJ , Montgomery Caj , Butel JS , Bradley A. , and Donehower LA (1993). Spontaneous and carcinogen-induced tumorigenesis in p53-deficient mice. Nat. Genet. 5: 225-229.

Johnson KA (1996). Foreign-body tumorigenesis: Sarcomas induced in mice by subcutaneously implanted transponders. Vet. Pathol. 33: 619 (abstract).

Kastan MB , Zhan Q. , el-Deiry WS , Carrier F. , Jacks T. , Walsh WV , Plunkett BS , Vogelstein B. , and Fornace Ajj (1992). A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587-597.

Kemp CJ , Wheldon T. , and Balmain A (1994). p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nat. Genet. 8: 66-69.

Kuwashima Y. , Nemoto N. , and Ishikawa T. (1993). Expression of proto-oncogenes and cytoskeletal actin gene in foreign body-induced murine sarcomas. In Vivo 7: 139-142.

Leder A. , Kuo A. , Cardiff RD , Sinn E. , and Leder P. (1990). v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: Effects of phorbol esters and retinoic acid. Proc. Natl. Acad. Sci. USA 87: 9178-9182.

10.

Mahler JF , Flagler ND , Malarkey DE , Mann PC , Haseman JK , and Eastin W. (1998). Spontaneous and chemically induced proliferative lesions in Tg.AC transgenic and p53-heterozygous mice. Toxicol. Pathol. 26: 501-511.

11.

National Cancer Institute (1979). Bioassay of p-Cresidine for Possible Carcinogenicity. Carcinogenesis Technical Report Series No. 142, National Cancer Institute, Bethesda, Maryland.

12.

Rao GN and Edmondson J. (1990). Tissue reaction to an implantable identification device in mice. Toxicol. Pathol. 18: 412-416.

13.

Robinson D. (1998). The International Life Sciences Institute's role in the evaluation of alternate methodologies for the assessment of carcinogenic risk. Toxicol. Pathol. 26: 474-475.

14.

Shi X. , Castranova V. , Halliwell B. , and Vallyathan V. (1998). Reactive oxygen species and silica-induced carcinogenesis . J. Toxicol. Environ. Health B Crit. Rev. 1: 181-197.

15.

Tennant RW , French JE , and Spalding JW (1995). Identifying chemical carcinogens and assessing potential risk in short-term bioassays using transgenic mouse models. Environ. Health Perspect. 103: 942-950.

16.

Tennant RW , Spalding JW , and French JE (1996). Evaluation of transgenic mouse bioassays for identifying carcinogens and non-carcinogens. Mutat. Res. 365: 119-127.

17.

Zakut-Houri R. , Oren M. , Bienz B. , Lavie V. , Hazum S. , and Givol D. (1983). A single gene and a pseudogene for the cellular tumour antigen p53. Nature 306: 594-597.