Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice

Abstract

Human rearranged RET/PTC3 (papillary thyroid carcinoma) proto-oncogene and high-risk human papillomavirus (HPV) type 16 E7 oncogene induces in the mouse a neoplastic transformation of thyroid follicular cells. We present a detailed immuno-histological study (170 mouse thyroids: RET/PTC3, E7, wild type, 2-to 10-month-old) with cell cycle proliferation and signalling pathway indicators. The characteristics of both models are different. There is an 'oncogene dependent' cellular signature, maintained at all studied ages in the E7 model, less in the RET/PTC3 model. During tumour development a large heterogeneity occurred in the Tg-RET/PTC3 model within a same tumour or within a same thyroid lobe. The Tg-E7 model was less heterogeneous, with a dominant goitrous pattern. The solid tumour already described in the RET/PTC3 models associated with cribriform patterns, suggested 'PTC spindle cell changes' as in humans PTC rather than the equivalent of the solid human PTC. Proliferation and apoptosis in the two thyroid models are related to the causal oncogene rather than reflect a general tumorigenic process. The thyroids of RET/PTC3 mice appeared as a partial and transient model of human PTCs, whereas the Tg-E7 mice do not belong to the usual PTC type.

Monocarboxylate transporter 8 deficiency: altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy

“…RET/PTC3-transgenic mice develop PTC with lymph node metastases (21). A careful and detailed histological comparison of RET/PTC3-and human papillomavirus type 16 E7-transgenic (Tg-E7) mice showed that RET/PTC3 mice appear as a partial and transient model of human PTCs, while human papillomavirus type 16 E7-transgenic mice present with a dominant goitrous pattern of thyroid changes (22). In younger Mct8…”

Signal transduction in the human thyrocyte and its perversion in thyroid tumors

“…This is further supported by the fact that expression of one oncogene (eg RET-PTC3) in the thyroid of mice elicits thyroid growth and dedifferentiation but not general carcinomas. In fact the thyroids of such mice get, gene expression wise, more and more different from human papillary carcinomas as they age (Burniat et al, 2008). However they develop different localized, then extensive lesions… obviously as the result of further localized oncogenic event.…”

“…Moreover the use of inducible tissue-specific knock-down or oncogene expression systems should allow a clearer dissection of carcinogenic pathways in vivo. However, transgenic mice expressing an oncogene in the thyroid (eg RET/PTC3) develop tumors whose morphology, gene expression and evolution are partly different from their human counterpart (Burniat et al, 2008;Jin et al, 2008).…”

“…The expression in thyroid of oncogene E7 of HPV-16, which sequestrates pRb protein, leads to thyroid growth and (partially dedifferentiated) euthyroid goiter (Burniat et al, 2008;Coppee et al, 1996). Expression in the thyroid of the adenosine A 2 receptor, which behaves as a constitutive activator of adenylyl cyclase, induces thyroid growth, goitrogenesis, and hyperthyroidism (Ledent et al, 1992).…”

Modeling Thyroid Cancer in the Mouse

“…Recently, microarray gene profiling was used to assess the similarity in the altered gene expression patterns between PTC in humans and RET/PTC3 mice [67,68]. Several human PTC characteristics were observed in RET/PTC3 mice: overexpression of many immune-related genes, regulation of human PTC markers, upregulation of EGF-like growth factors and significant regulation of angiogenesis, and extracellular matrix remodeling-related genes [67, 68].…”