Genetic Alterations in Thyroid Cancer: The Role of Mouse Models

Knostman, Katherine A. B.; Jhiang, Sissy; Capen, Charles C.

doi:10.1354/vp.44-1-1

Cited by 24 publications

(20 citation statements)

References 80 publications

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“…Differences between thyroid cancer prone mouse strains have been demonstrated by others (Knostman et al, 2007). In our thyroid transgenics this phenomenon might explain strain-tostrain alterations (Russell et al, 2004;Knostman et al, 2007) as well as a detectable background of thyroid neoplasia.…”

Section: Discussionsupporting

confidence: 75%

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

et al. 2008

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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.

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Section: Discussionsupporting

confidence: 75%

“…In our thyroid transgenics this phenomenon might explain strain-tostrain alterations (Russell et al, 2004;Knostman et al, 2007) as well as a detectable background of thyroid neoplasia.…”

Section: Discussionmentioning

confidence: 75%

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

et al. 2008

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“…Alternatively, Mct8 may be involved in the export from thyrocytes of toxic metabolites, although there is as present no indication of any Mct8 substrate other than iodothyronines. Several genetic alterations are observed in thyroid cancer and have guided the generation of respective mouse models (19). These include germline or somatic mutations in BRAF (20) and RET (21).…”

Section: Discussionmentioning

confidence: 99%

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

Wirth

Sheu

Chiu-Ugalde

et al. 2011

European Journal of Endocrinology

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Context: Thyroid hormone transport across the plasma membrane depends on transmembrane transport proteins, including monocarboxylate transporter 8 (MCT8). Mutations in MCT8 (or SLC16A2) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma triiodothyronine (T 3 ) and low/normal thyroxine (T 4 ). MCT8 contributes to hormone release from the thyroid gland. Objective: To characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice. Design: Thyroid morphology in a patient carrying the A224V mutation was followed by ultrasound imaging for over 10 years. After thyroidectomy, a histopathological analysis was carried out. The findings were compared with histological analyses of mouse thyroids from the Mct8 K/y model. Results: We show that an inactivating mutation in MCT8 leads to a unique, progressive thyroid follicular pathology in a patient. After thyroidectomy, histological analysis revealed gross morphological changes, including several hyperplastic nodules, microfollicular areas with stromal fibrosis and a small focus of microfollicular structures with nuclear features reminiscent of papillary thyroid carcinoma (PTC). These findings are supported by an Mct8-null mouse model in which we found massive papillary hyperplasia in 6-to 12-month-old mice and nuclear features consistent with PTC in almost 2-year-old animals. After complete thyroidectomy and substitution with levothyroxine (L-T 4 ), the preoperative, inadequately low T 4 and free T 4 remained, while increasing the L-T 4 dosage led to T 3 serum concentrations above the normal range. Conclusions: Our results implicate peripheral deiodination in the peculiar hormonal constellation of MCT8-deficient patients. Other MCT8-deficient patients should be closely monitored for potential thyroid abnormalities.

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“…The TRK-T1 transgenic mouse model was important as in vitro TRK-T1 cannot transform cells, and therefore, it was not clear as to its importance in thyroid cancer. About half of the transgenic mice that expressed TRK-T1 developed thyroid cancer, either FTC or PTC, without distant metastasis (15). When crossed with knockout mice of the cell cycle inhibitor, p27, these double-mutant mice developed thyroid cancers at an earlier age (52).…”

Section: Ntrk1mentioning

confidence: 99%

“…The mouse strain B6C3F1, frequently used in bioassay and carcinogenicity studies, has a very low incidence of spontaneous thyroid cancer development, which makes it difficult to incorporate in studies (15). There are three general approaches for inducing tumors: carcinogenic compounds, implantation of tumor cells via a subcutaneous or orthtotopic route in immunocompromised mice, or genetically engineered models.…”

Section: Introductionmentioning

confidence: 99%

Lessons from Mouse Models of Thyroid Cancer

Kim

Zhu

2009

Thyroid

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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 thyrotropinregulated 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.

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Genetic Alterations in Thyroid Cancer: The Role of Mouse Models

Cited by 24 publications

References 80 publications

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

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

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

Lessons from Mouse Models of Thyroid Cancer

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