Acceleration of BRAFV600E-induced thyroid carcinogenesis by TGFβ signal deficiency in mice

• Published in: Endocrine 2020-09, Vol.69 (3), p.571-577
• Main Authors: Shimamura, Mika, Kurashige, Tomomi, Kuatov, Rassul, Nakashima, Masahiro, Nagayama, Yuji
• Format: Article
• Language: English
• Subjects: Carcinogenesis; Diabetes; E-cadherin; Endocrinology; Humanities and Social Sciences; Inclusion bodies; Internal Medicine; Medicine; Medicine & Public Health; Mesenchyme; multidisciplinary; Original Article; Rodents; Science; Signal transduction; Thyroglobulin; Thyroid cancer; Transforming growth factor-b; Tumors; Vimentin
• ISSN: 1355-008X; 1559-0100
• DOI: 10.1007/s12020-020-02298-1

Purpose Transforming growth factor-β (TGFβ) has pleiotropic actions, including both anti- and pro-tumorigenic abilities. We have previously shown no tumor development in the thyroid-specific TGFβ receptor type II knockout ( Tgfβr2 KO) mice, indicating the insufficiency of defective TGFβ signal itself for thyroid cancer initiation. In the current study, we evaluated whether defective TGFβ signal accelerates BRAF V600E -mediated thyroid carcinogenesis in our mouse model, in which intrathyroidal injection of adenovirus expressing Cre under thyroglobulin (TG) promoter (Ad-TgP-Cre) into thyroid lobes of conditional Braf V600E knock-in mice ( Braf CA ) induces thyroid cancers 12 months later. Methods Braf CA/wt ; Tgfbr2 floxE2/floxE2 mice were generated by crossing Tgfbr2 floxE2/floxE2 and Braf CA mice, and Ad-TgP-Cre was injected into the left lobes of 4–6-week-old mice. Mice were sacrificed at 6 and 12 months, and the thyroid tissues were subjected to H&E and immune-histochemistry and -fluorecence. Results Thyroid tumors were observed in 8 of 10 mice at 6 months and 4 of 7 mice at 12 months. These tumors were judged to be malignant by H&E staining, because of the presence of papillary growth of atypical follicular cells, intranuclear cytoplasmic inclusions and so on. Immunohistochemical analyses using thyroid cancer tissues obtained at 6 months demonstrated variable levels of TG but steady levels of Paired Box-8 expression and higher Ki67 positivity. The degree of epithelial-to-mesenchymal transition could not be evaluated because normal thyroid tissues and thyroid cancers developed in Braf CA and Braf CA/wt ; Tgfbr2 floxE2/floxE2 mice were all E-cadherin + /vimentin − , that is, epithelial type. Conclusion In a mouse model, defective TGFβ signaling pathway accelerates BRAF V600E -induced thyroid cancer development, which is occasionally accompanied by reduced TG expression implying dedifferentiation. The former finding is consistent with anti-tumorigenic ability of TGFβ in early tumorigenic process, but the latter is contradictory to generally accepted concept for TGFβ-induction of dedifferentiation.