Thymic epithelial tumour progression in an SV40T transgenic mouse model

Abstract

There have been several reports that thymoma in human is a progressive disease, and that thymoma and thymic carcinoma form a continuum. We established a stable line of SV40T transgenic mice, which consistently produced thymic epithelial tumours progressing to thymic carcinoma within a predictable time span. Using this animal model and a morphological approach, thymic epithelial tumour progression was studied with reference to sequential changes at different time points in animals aged from 3 to 32 weeks. At all ages, SV40T was expressed in the nuclei of thymic epithelial cells; in these transgenic mice we observed the entire spectrum from cortical type thymoma to thymic carcinoma. Thymic size tended to increase with ageing in SV40T TG mice. While younger mice had predominantly cortical (organoid) or cortical thymoma, older mice had well-differentiated thymic carcinoma (WDTC) or poorly differentiated thymic carcinoma. When SV40T TG mice (248 line) reached a certain age, carcinoma of the thymus was present in all of them. Cortical-type thymoma became malignant within a predictable time span, suggesting a cortical thymoma-carcinoma sequence. When the mice were 9 weeks of age, the thymuses formed gross masses compatible with cortical thymoma. At 14 weeks of age, WDTC appeared against the background of cortical thymoma. Poorly differentiated thymic carcinoma was found after 15 weeks and affected all animals over 23 weeks of age. Most thymic carcinomas coexisted in varying proportions with cortical-type thymoma. Medullary thymomas did not develop in the mice, and no transition from medullary-type thymomas to thymic carcinomas was observed. In this SV40T transgenic mouse model, thymic carcinoma is clearly preceded by cortical-type thymoma. These transgenic mice may provide an interesting model for the progression from cortical thymoma to WDTC and/or high-grade carcinoma.

High Incidence of Thymic Epithelial Tumors in E2F2 Transgenic Mice

“…INK4A /pRb and p53 pathway is essential to bypass the senescence checkpoint in human epithelial cells (56), and inactivation of both pathways contributes to the onset of thymic epithelial tumors in SV40 large T and human papillomavirus 16 E6/E7 transgenic mice (57,58). These data suggest that mutation of p53/MDM2/p19ARF pathway could be a rate-limiting step for the induction of cortical thymomas in E-pp-E2F2 mice.…”

Thymoma related myasthenia gravis in humans and potential animal models

“…In wild mice, thymomas are virtually non-existent, but develop almost consistently after thymic epithelial cell directed transgenic expression of the E2F2 transcription factor [97], SV40 large T-antigen [98,99] or mutant K-Ras2 [100]. A problem with the latter models is that the clonal nature of the induced thymomas is questionable, since they mostly develop after a period of organ-wide thymic (epithelial) hyperplasia.…”

Early Steps of a Thymic Tumor in SV40 Transgenic Mice: Hyperplasia of Medullary Epithelial Cells and Increased Mature Thymocyte Numbers Disturb Thymic Export

“…Today only one team has described a thymic carcinoma issued of an extanded thymic hyperplasia in Tg mice made with SV40 Simian Virus T antigen 40 (SV40) associated with it own promoter (Park et al, 1996;Lee et al, 1998).…”