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

Area of Science:

• Oncology
• Molecular Biology
• Pathology

Background:

• Papillary thyroid carcinoma (PTC) is a common endocrine malignancy.
• Investigating oncogenic drivers like RET/PTC3 and HPV16 E7 is crucial for understanding thyroid tumorigenesis.
• Mouse models are essential for studying cancer development and evaluating therapeutic strategies.

Purpose of the Study:

• To compare the distinct neoplastic transformations induced by the human RET/PTC3 proto-oncogene and the high-risk human papillomavirus (HPV) type 16 E7 oncogene in mouse thyroid follicular cells.
• To analyze cell cycle proliferation and signaling pathway indicators in these mouse models.
• To evaluate the fidelity of these models in recapitulating human thyroid cancer.

Main Methods:

• Detailed immunohistological study of 170 mouse thyroids across different age groups (2-10 months).
• Analysis included mice with RET/PTC3, E7 oncogene expression, and wild-type controls.
• Assessment of cell cycle proliferation and key signaling pathway indicators.

Main Results:

• The RET/PTC3 and E7 oncogenes induced distinct thyroid neoplastic transformations with differing cellular signatures and heterogeneity.
• The Tg-RET/PTC3 model exhibited significant tumor heterogeneity and changes suggestive of human PTC spindle cell alterations.
• The Tg-E7 model showed less heterogeneity with a dominant goitrous pattern, not typical of human PTC.
• Proliferation and apoptosis were oncogene-dependent, not general tumorigenic processes.

Conclusions:

• The RET/PTC3 mouse model partially and transiently recapitulates aspects of human papillary thyroid carcinoma.
• The Tg-E7 mouse model does not represent a typical form of human papillary thyroid carcinoma.
• These distinct models provide valuable tools for studying thyroid cancer pathogenesis driven by specific oncogenes.