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Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53−/− mice

Oncogene volume 20, pages 3235–3246 (2001)Cite this article

Abstract

Cancers develop and progress via activation of oncogenes and loss of tumor suppressor genes, a progression that can be recapitulated through cross breeding mouse strains harboring genetic mutations. To define the role of RET/PTC3, p53 and Fhit in thyroid carcinogenesis, we intercrossed RET/PTC3 transgenics with p53−/− mice. This new strain, RET/PTC3p53−/−, succumb to rapidly growing and strikingly large multilobed thyroid tumors containing mixtures of both well and poorly differentiated, highly proliferative follicular epithelial cells. Interestingly, transplanted tumors from RET/PTC3p53−/− mice grew in SCID but not syngeneic immunocompetent mice indicating that these advanced tumors were immunogenic. RET/PTC3 protein expression was reduced to undetectable levels in tumors of older mice suggesting that the continued elevated expression of RET/PTC3 may not be necessary for tumor progression. Similarly, expression of Fhit protein was reduced in early tumors and undetected in older tumors irrespective of tumor histopathology. In contrast to RET/PTC3p53−/− mice, RET/PTC3Fhit−/− mice did not develop advanced thyroid carcinomas. These studies support a model of human thyroid cancer whereby thyroid epithelium expresses RET/PTC3 protein at early stages of tumor development, followed by the reduction of RET/PTC3 and loss of p53 function with progressive reduction of Fhit protein expression coincident with malignant progression.

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Abbreviations

PTC:

papillary thyroid carcinoma

SCID:

severe combined immunodeficient.

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Acknowledgements

We thank the Kimmel Cancer Institute Transgenic Animal Facility for assistance in the development of transgenic mice and the Nucleic Acid Facility for oligonucleotide synthesis and DNA sequencing. This work was supported by grants from the National Institutes of Health CA21124 and CA76259 (JL Rothstein), T32-AI07492 (DJ Powell), T32-CA09678 (JP Russell) and T32-CA72318 (BA Kuo).

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  1. Department of Microbiology/Immunology and Otolaryngology-Head & Neck Surgery, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, 19107, Pennsylvania, PA, USA

    Daniel J Powell Jr, John P Russell, Guoqi Li, Bruce A Kuo, Vincenzo Fidanza, Kay Huebner & Jay L Rothstein

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Powell Jr, D., Russell, J., Li, G. et al. Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53−/− mice. Oncogene 20, 3235–3246 (2001). https://doi.org/10.1038/sj.onc.1204425

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