Lessons from mouse models of thyroid cancer

Abstract

Background: Thyroid cancer is the most common endocrine tumor and is increasing in incidence. The aim of this study was to review mouse models of differentiated thyroid cancer and how they elucidate human thyroid cancer biology.

Summary: Differentiated thyroid cancer, primarily papillary and follicular, comprises the majority of thyroid cancers. There has been tremendous growth in the cross-talk between basic science and clinical practice for thyroid cancer management. Insight into the framework of genes responsible for differentiated thyroid cancer has been gained through the use of mouse models. Common genetic alterations found in human papillary thyroid cancer such as RET/PTC rearrangements or the BRAF(V600E) mutation have genetically modified mouse counterparts. These and other preclinical mouse models have validated the importance of the cyclic adenosine monophosphate (cAMP)/protein kinase A and mitogen-activated protein kinase (MAPK) signaling pathways in papillary thyroid cancer (PTC). RAS mutations have a role in both papillary and follicular thyroid cancer development. Mice with overactivation of the phosphatidylinol-3-kinase (PI3K)-AKT and/or thyrotropin-regulated signaling pathways have been found to develop follicular thyroid cancer. Additional mouse models of thyroid cancer that utilize inducible expression systems are in development or are being characterized and will better reflect the majority of human thyroid cancers which are non-hereditary. Advances in in vivo imaging of mice allow for earlier detection of metastasis and the ability to follow tumor growth or regression which may be used in evaluation of pharmaceutical agents.

Conclusions: Mouse models have expanded our understanding of the altered signaling pathways that contribute to thyroid cancer tumorigenesis and provide a powerful tool to develop novel diagnostic approaches and therapies.

FIG. 1.

Examples of genetically engineered mice utilizing thyroid-specific promoters and Cre recombinase. (A) Thyroid-specific expression of an oncogene. The oncogenic target gene is placed downstream of a stop signal flanked by two loxP sites preventing its expression. Excision of the stop cassette with Cre recombinase allows target gene expression only in the thyroid. (B) Knockdown of a tumor suppressor gene by its excision through Cre recombinase. Cre is under control of a thyroid-specific promoter (like thyroglobulin) and its expression restricted to the thyroid, resulting in gene knockdown only in the thyroid. (C) Spatial and temporal gene expression by using a conditional inducible Cre recombinase. Cre is fused to the ligand binding domain of the estrogen receptor (ER) that can only bind to tamoxifen and not estrogen (ER-Tamoxifen). Cre is active only in the presence of tamoxifen and the target gene is only expressed in the thyroid due to its tissue-specific promoter.

FIG. 2.

Altered signaling pathways and mouse models of thyroid cancer. Mouse models are indicated by an (*). Aberrant signaling through receptor tyrosine kinases (RTK) such as the RET and NTRK1 receptors induce papillary thyroid cancer (PTC). Overactivation of the RAS/RAF/MEK/ERK pathway (or MAPK signaling pathway) leads to PTC. The BRAF^V600E mutation results in constitutive activation of BRAF and is commonly found in PTC. RAS overactivation is common to both papillary and follicular thyroid cancer (FTC) models. TSH receptor (TSHR) signaling via adenyl cyclases/cAMP/protein kinase A (PKA) is important for normal thyroid growth, but only a few models of TSHR overactivation develop thyroid cancer (Prkar1a^Δ2/⁺, Rap1b^G12V). The adrenergic receptor may also contribute to thyroid cancer development also through increased cAMP and signaling via pathways such as MAPK and protein kinase C (PKC). Overactivation in the PI3K-AKT signaling pathway via cell-surface receptors such TSHR or inactivation of the phosphatase, PTEN, are important for FTC tumorigenesis. TRß^PV/PV mice also have PI3K-AKT overactivation and develop FTC. Please see text for additional details regarding these mouse models.

Fig. 3.

Tg-BRAF2 mice recapitulate papillary thyroid cancer (low-magnification, A), with overlapping, enlarged nuclei with nuclear grooves (B, arrow). Poorly differentiated carcinomas also develop (C) as well as tumors with aggressive features of tumor progression such as vascular invasion (D, arrow). Adapted from Figure 4 of Ref. (27). This figure was kindly provided by Drs. Jeffrey A. Knauf and James A. Fagin.

Fig. 4.

TRβ^PV/PV mice recapitulate follicular thyroid cancer with capsular and vascular invasion (panels A and B respectively, arrows). Dedifferentiation can be found (panel C) along with distant metastasis to lung (panel D, arrow). Reproduced from Ref. (83). This figure was kindly provided by Dr. Sheue-Yann Cheng.