Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas.
Papillary thyroid carcinomas in humans are associated with the ret/PTC oncogene and, following loss of p53 function, may progress to anaplastic carcinomas. Mice with thyroid-targeted expression of ret/PTC1 developed papillary thyroid carcinomas that were minimally invasive and did not metastasize. These mice were crossed with p53-/- mice to investigate whether loss of p53 would promote anaplasia and metastasis of ret/PTC1-induced thyroid tumors. The majority of p53-/- mice died or were euthanized by 17 weeks of age due to the development of thymic lymphomas, soft tissue sarcomas, and testicular teratomas. All ret/PTC1 mice developed thyroid carcinomas, but tumors in p53-/- mice were more anaplastic, larger in diameter, more invasive, and had a higher mitotic index than tumors in p53+/+ and p53+/- mice. Thyroid tumors did not metastasize in any of the experimental p53+/+ and p53+/- mice </=28 weeks of age or p53-/- mice </= 17 weeks of age; however, an older (170-day-old) male p53-/- mouse used to maintain the colony developed anaplastic thyroid carcinoma with liver metastases. These findings demonstrate that the lack of functional p53 in ret/PTC1 mice promotes anaplasia and invasiveness of thyroid carcinomas.
Department of Veterinary Biosciences and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
K M
KM
La Perle
S M
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Jhiang
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Capen
D000708:Anaplasia; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008940:Mitotic Index; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011505:Protein-Tyrosine Kinases; D013961:Thyroid Gland / Q000378:metabolism* / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D015514:Oncogene Proteins, Fusion; D016159:Tumor Suppressor Protein p53; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human