Genetic Alterations in Thyroid Cancer: The Role of Mouse Models

Vet Pathol 44:1–14 (2007) Genetic Alterations in Thyroid Cancer: The Role of Mouse Models K. A. B. KNOSTMAN, S. M. JHIANG, AND C. C. CAPEN Departm...
Author: Easter Johns
5 downloads 0 Views 616KB Size
Vet Pathol 44:1–14 (2007)

Genetic Alterations in Thyroid Cancer: The Role of Mouse Models K. A. B. KNOSTMAN, S. M. JHIANG,

AND

C. C. CAPEN

Departments of Veterinary Biosciences (KABK, CCC) and Physiology and Cell Biology (SMJ), The Ohio State University, Columbus, OH Abstract. Thyroid carcinomas are the most common endocrine neoplasms in humans, with a globally increasing incidence. Thyroid follicular cells and neuroendocrine (parafollicular) C cells are each susceptible to neoplastic transformation, resulting in thyroid cancers of differing phenotypes with unique associated genetic mutations and clinical outcomes. Over the past 15 years, several sophisticated genetically engineered mouse models of thyroid cancer have been created to further our understanding of the genetic events leading to thyroid carcinogenesis in vivo. The most significant mouse models of papillary, follicular, anaplastic, and medullary thyroid carcinoma are highlighted, with particular emphasis on the relationship between the relevant oncogenes in these models and genetic events in the naturally occurring human disease. Limitations of each model are presented, and the need for additional models to better recapitulate certain aspects of the human disease is discussed. Key words:

endocrine; mice; Neoplasm; thyroid.

Thyroid carcinomas are the most common endocrine neoplasms in humans, affecting approximately 1% of the population.77 Roughly 95% of all thyroid tumors are of thyroid follicular epithelial cell origin, including papillary, follicular, and anaplastic thyroid carcinomas. The remaining 5% are medullary thyroid carcinomas of C cell origin.17,77 The subclassification of thyroid cancers into these 4 categories is clinically significant. Papillary thyroid carcinomas metastasize via lymphatics to local lymph nodes in an estimated 50% of cases but have the most favorable prognosis, with a 98% 10-year survival rate. Follicular and tall cell variants of papillary thyroid carcinoma are associated with poorer prognoses. Follicular thyroid carcinomas are more prevalent in areas of dietary iodine deficiency, metastasize hematogenously, and are less likely than papillary thyroid carcinomas to take up radioactive iodide for imaging and therapeutic ablation. However, the 10-year survival rate for follicular thyroid carcinomas is still high at 92%. Anaplastic thyroid carcinomas are almost invariably fatal as a result of rapid invasion of critical structures in the neck, distant metastases, and a failure to take up radioactive iodide. In many cases, anaplastic thyroid carcinomas arise from dedifferentiation of follicular or papillary carcinomas or in patients with a history of multinodular goiter.17 Medullary thyroid carcinomas, also commonly known as C-cell carcinomas, arise from calcitoninsecreting C cells and are associated with inherited

syndromes, such as multiple endocrine neoplasia (MEN), in approximately 20%–25% of cases.17,77 Medullary carcinomas frequently metastasize via the bloodstream, in addition to lymphatic spread, and are treated with surgical resection and/or external beam radiation. In contrast to follicularorigin thyroid tumors, C cells and tumors arising from them do not have the ability to take up radioactive iodide. The 5-year survival rate for medullary thyroid carcinomas is approximately 50%. According to the National Cancer Institute Surveillance Epidemiology and End Results (SEER) data, as well as other studies, thyroid cancer is one of the few cancer types with increasing incidence in the United States and around the globe, particularly among women.76 Genetic Events in Thyroid Tumors of Follicular Cell Origin Thyroid follicular cells are responsible for iodide uptake and thyroid hormone synthesis and can undergo neoplastic transformation to carcinomas of 3 histotypes: papillary, follicular, and anaplastic. It is well-known that papillary thyroid carcinomas can occur secondary to ionizing radiation exposure, particularly in children.6,53,77 After the Chernobyl nuclear reactor accident in 1986, the incidence of thyroid carcinomas in children in affected areas of Belarus increased from less than 1 per million to more than 90 per million.10 The primary known molecular mechanism of radiation-induced papillary carcinoma development is through the Ret/ 1

2

Knostman, Jhiang, and Capen

PTC group of oncogenes. Ret proto-oncogene is a receptor tyrosine kinase normally involved in the glial-derived neurotropic factor-signaling pathway in neuroendocrine and neural cells. In thyroid follicular cells, the alignment of chromosomes during interphase places the ret proto-oncogene in close proximity to several other constitutively expressed genes with which it can recombine during repair of ionizing radiation–induced double-stranded DNA breaks.53,55 These Ret/PTC rearrangements allow for unregulated expression of chimeric oncoproteins with constitutive tyrosine kinase activity. Ret/PTC expression is found in roughly one third of all papillary carcinomas, but in the majority of all radiation-induced papillary carcinomas.39 While Ret/PTC1-expressing papillary carcinomas are often well differentiated, Ret/ PTC3 expression is associated with a solid phenotype and a more aggressive clinical course.53,90 Sporadic papillary thyroid carcinomas unrelated to radiation exposure make up more than two thirds of all cases, and several genetic events have been identified as important in their tumorigenesis.54 A form of the B-type Raf kinase, or BRAF, with a point mutation resulting in V600E has been identified in approximately 45% of sporadic papillary carcinomas, particularly the tall-cell variant.92 BRAF expression has been associated with dedifferentiation and disease progression. NTRK1 is a receptor tyrosine kinase normally involved in nerve growth factor signaling.83 Like Ret/PTC rearrangements, NTRK1 can recombine with the 59 end of other heterologous genes and form a constitutively active oncogene, such as TRK-T1, leading to papillary carcinomas. However, NTRK1 rearrangements are less frequent than Ret/PTC rearrangements and are not associated with radiation exposure. Finally, chromosomal rearrangement of the PTEN tumor-suppressor gene leading to its loss of function has been recently associated with papillary carcinoma formation.60 Ras mutations have been implicated in the development of follicular thyroid carcinomas, particularly N-ras activating mutations at codon 61.54,86,89 Expression of a Pax8-PPARc fusion protein has been detected in a small number of follicular carcinomas and follicular variants of papillary carcinomas.42,43 While controversy exists over the ability of chronic thyroid stimulating hormone (TSH) stimulation to result in thyroid tumorigenesis, follicular carcinomas are most prevalent in iodine-deficient regions, suggesting that TSH stimulation may play a role.24,45,68,89 An elevation in the risk of thyroid tumorigenesis in patients with certain types of goiter has been

Vet Pathol 44:1, 2007

reported,24,50,67,85 although there is a lack of consensus regarding this association. Loss of p53 function is the primary genetic alteration identified in the development of anaplastic thyroid carcinomas,30,54,63 although BRAF and Ret/PTC3 mutations have been associated with some degree of anaplasia in papillary carcinomas.54,92 b-catenin activating mutations have also been detected in anaplastic thyroid carcinomas, where the protein likely mediates loss of cell-cell adhesions and also acts as a transcription factor in upregulating growth-promoting genes.25 Genetic Events in Thyroid Tumors of C Cell Origin Medullary thyroid carcinomas, or C-cell carcinomas, arise from the calcitonin-secreting parafollicular C cells of the thyroid gland. These tumors can occur as part of an inherited syndrome, such as MEN type 2A or type 2B or familial medullary thyroid carcinoma, which together account for 20%–25% of all medullary thyroid carcinomas.17,61,77 The ret proto-oncogene, which can undergo rearrangements in papillary carcinoma as previously described, is also important in initiating medullary carcinoma. In medullary carcinoma, the full-length ret proto-oncogene has gain-of-function point mutations involving 1 of several possible codons.19,52,61 As a result, Ret is constitutively active in the neuroendocrine tissues normally expressing this protein, such as thyroid C cells and neuroendocrine cells of the adrenal medulla. All of the known hereditary forms of medullary carcinoma are autosomal-dominant and involve ret mutations. While sporadic medullary carcinomas comprise more than 75% of cases, little is known about specific genetic mutations initiating this form of thyroid cancer. However, somatic ret point mutations have been identified in up to 50% of sporadic cases.27 Animal Models of Thyroid Cancer Thyroid cancer arises as a spontaneous disease in domestic animal species, particularly follicular adenomas in cats, solid-to-follicular carcinomas in dogs, and C-cell (ultimobranchial) carcinomas in bulls.5,9,64 However, the incidence of tumorigenesis in these species is too low for feasible use as experimental models of the human disease, and the genotypic similarities to the human disease remain unclear. Many xenobiotics result in thyroid tumors of follicular cell origin in laboratory mice and rats, generally by lowering thyroxine (T4) levels, leading to an increase in circulating TSH and thyroid follicular cell proliferation.9 Some of the implicated

Vet Pathol 44:1, 2007

Mouse Models of Thyroid Cancer

compounds include hepatic Cyp2B inducers, thyroperoxidase and 59-deiodinase inhibitors, and inhibitors of the sodium/iodide symporter.8 This pathway of thyroid tumorigenesis is believed to be much less important in humans than in rodents, as the half-life of thyroid hormones is 5–18 times greater in humans than in rodents because of the presence of the transport protein thyroxine-binding globulin in circulation.8 Thus, the shorter half-life of thyroid hormones in rodents results in greater ease of disruption of thyroid hormone homeostasis. In the B6C3F1 laboratory mouse strain, which is commonly used in long-term toxicity studies, thyroid tumorigenesis occurs in 1%–10% of females and 0.8% of males by age 24 months (Charles River Laboratories, www.criver.com). However, the incidence rate and distribution of tumor types make these spontaneous models insufficient for use in mechanistic studies of thyroid cancer. The majority of published studies utilizing mouse models of thyroid cancer have involved xenografts of human thyroid tumor tissue or immortalized thyroid carcinoma cell lines into severe combined immunodeficient (SCID) mice. SCID mouse tumor xenograft models have several drawbacks, including tumor implantation into an artificial microenvironment, rare success of metastasis from a subcutaneous location, lack of normal B- and T-cell function for evaluation of immune components of disease, and frequent onset of multiple spontaneous neoplasms.2 Attempts to address these drawbacks in thyroid models have included orthotopic implantation of a thyroid carcinoma cell line into the mouse thyroid gland,20,37 selection of an anaplastic thyroid carcinoma cell line for pulmonary metastatic ability by serially passaging through nude mice,97 and implantation of human peripheral blood lymphocytes into a SCID mouse model of thyroid carcinoma to confer partial immune competence.28 The most commonly used cell lines in SCID mouse models of thyroid cancer include papillary thyroid carcinoma cell lines and NPA;16,56 follicular thyroid carcinoma cell lines FTC-133, FTC-238, RTC-R2 and FRO;26,74,79,84 anaplastic thyroid carcinoma cell lines ARO, DRO, WRO, KAT-4, and Thena;3,11,20,31,32,57,72,78,87,88,94,95,97 and medullary thyroid carcinoma cell lines TT and rMTC.4,21,41,51,62,80,81,93 Genetically Engineered Mouse Models of Thyroid Cancer Genetically engineered mouse models of thyroid cancer facilitate analysis of the roles of specific genetic mutations in thyroid tumorigenesis. Because thyroid cancer truly encompasses several

3

diseases with different etiologies and relevant genetic mutations, no single transgenic mouse model of thyroid cancer can fully recapitulate the full spectrum of disease. However, several models have successfully reproduced various aspects and have offered insight into genetic mutations underlying thyroid tumorigenesis. These mouse models of thyroid cancer offer examples of positive genotype-phenotype correlation. Over the past decade, several genetically engineered mouse models of thyroid cancer have been utilized to replicate variants of the human disease (Tables 1, 2). In most cases, transgenic mice have been produced using the highly active bovine thyroglobulin (Tg) promoter to specifically target transgene expression to thyroid follicular cells or using the human or rat calcitonin/calcitonin generelated peptide (CGRP) promoter to target transgene expression to C cells. In some cases, tumor suppressor gene knockout mice have been created and cross-bred with transgenic mice expressing thyroid-specific oncogenes, resulting in increased tumorigenesis and/or an aggressive phenotype. Mouse Models of Papillary Thyroid Carcinoma Tg-Ret/PTC1

FVB/N strain transgenic mice expressing thyroid-targeted Ret/PTC1 tyrosine kinase consistently developed bilateral papillary thyroid carcinomas with similar histopathologic features to the human disease, including papillary folds, ground-glass nuclei, and nuclear invaginations (Figs. 1–3).33 Tumorigenesis was abolished when all 3 critical phosphotyrosine residues involved in signaling pathways mediated by Ret/PTC1 were mutated, but not when single residues were mutated, although tumor incidence was decreased.7 Thus, signaling pathways mediated by each single phosphotyrosine residue were not solely essential for tumor development, but all 3 worked in concert to induce tumorigenesis. Like the human disease, these tumors accumulated less radioactive iodide than did normal thyroid tissue. The severity of disease varied markedly between high- and lowcopy founder lines. High-copy lines had dysplastic thyroid glands at birth and developed carcinomas as young as 4 days of age, as compared with 1– 6 months of age in the low-copy line.13,71 Mice from the high-copy line were profoundly hypothyroid, as indicated by low serum T4 and triiodothyronine (T3) levels, dwarfism, infertility, paraphimosis, and hyperplasia of TSH-secreting pituitary thyrotrophs. Hypothyroidism likely resulted from either a dedifferentiating effect of the Ret/PTC1 oncogene on thyroid follicular cells or

4

Knostman, Jhiang, and Capen

Table 1.

Summary of genetically engineered mouse models of thyroid cancer. Evidence of Tumor Aggressiveness*

Model

Tg-Ret/PTC1 Tg-Ret/PTC1 3 p532/2 Tg-Ret/PTC3 Tg-Ret/PTC3 3 p532/2 Tg-BRAFV600E Tg-TRK-T1 Tg-c-Ha-ras TRbPV/PV or PV/2 Tg-Rap1bG12V Tg-SV40 LT CGRP-Ret Rb+/2 and Rb+/2 p53+/2 CGRP-v-Ha-ras

Vet Pathol 44:1, 2007

Tumor Type Anaplasia Local Invasion

Metastasis

Papillary Papillary

Y{ Y

Y Y

None Liver{

Papillary Papillary

Y Y

Y Y

Lymph node{ Lymph node{

Papillary (tall cell) Papillary Papillary Follicular

Y

Y

None

Y N Y

NR NR Y

None Lung Lung, heart

Follicular Anaplastic Medullary Medullary

N Y N N

Y Y Y N

Medullary

N

Y

Hormonal Derangement

Hypothyroidism Hypothyroidism

Reference

13, 33, 71, 73 44

NR NR

58 59

High TSH euthyroid

40, 92

None None High TSH, T3 and T4 with TR resistance None Hypothyroidism{ Lung Hypothyroidism Liver{ Hypercalcitonism Lung, liver, lymph NR node, adrenal Lung, lymph node NR

70 69 35, 36, 82 66 46 19, 52, 65 18, 29, 96 34

* Y 5 yes; N 5 no; NR 5 not reported. { Rare. { Goitrogen treatment

reduced thyroglobulin synthesis due to competition for transcription factors between the endogenous Tg promoter and the highly active bovine Tg promoter used to drive transgene expression. Maintaining the mice on a low iodide diet resulted in persistent elevation of TSH levels and enhanced tumorigenesis.71 The elevation of TSH levels and TSH responsiveness of the Tg-Ret/PTC1 transgene is a drawback to this model, as chronic TSH stimulation is not believed to be involved in papillary carcinoma development in humans.90 The lack of any metastases is also a limitation to this model, although cross-breeding Tg-Ret/PTC1 mice with p532/2 mice did result in rare metastases, in addition to a more anaplastic phenotype, larger primary tumor size, and enhanced local invasion (Figs. 4–6).44 When a second research group independently created Ret/PTC1-expressing mice using the less active rat thyroglobulin promoter and a C57BL/6J background strain, less than half of the mice developed tumors after a long latent period (8–16 months).73 Tg-Ret/PTC3

Thyroid-targeted Ret/PTC3 tyrosine kinase expression led to the follicular cell hyperplasia and development of a solid variant of papillary thyroid carcinoma in almost all C3H/He strain transgenic

mice by the age of 6 months.58 Metastases to cervical lymph nodes did occur in this model, albeit rarely (less than 10%). Ret/PTC3–induced thyroid tumors did not dedifferentiate into the more aggressive phenotype often seen in human patients with Ret/PTC3 chromosomal rearrangements. Cross-breeding Tg-Ret/PTC3 transgenic mice with p532/2 mice resulted in earlier onset of tumorigenesis, with microcarcinoma formation by the age of 3 months and the development of primary tumors up to 285 times the mass of wild-type mouse thyroid glands.59 However, metastases were still rare in the p532/2 crosses, and progression did not occur to an anaplastic phenotype. Tg-BRAFV600E

Transgenic mice of the FVB/N strain with thyroid targeted BRAFV600E serine/threonine kinase expression developed multifocal bilateral papillary thyroid carcinomas between the ages of 12 and 22 weeks.40,92 Features of the human tall cell variant, which is characterized by tall columnar cells with intensely eosinophilic cytoplasm,17 were present in approximately half of the tumors. Foci of anaplasia were noted arising within and adjacent to well-differentiated papillary tumors, although there was no evidence of the necrosis commonly seen in human anaplastic carcinomas. In a high-

Vet Pathol 44:1, 2007

Mouse Models of Thyroid Cancer

5

expression transgenic line, tumors frequently invaded the surrounding fibrovascular tissue, sometimes leading to tracheal compression, but did not metastasize. Similar to the high-copy Tg-Ret/PTC1 mice, high-expression Tg-BRAF mice developed thyroid hormone derangements at a young age. However, in contrast to the Tg-Ret/PTC1 model, Tg-BRAF mice remained euthyroid and developed large goiters as a compensatory response to the high circulating TSH levels.

retinoblastoma (Rb) function,47 or the adenosine A2b receptor, which stimulates cAMP signaling.14,15,48 Coexpression of both transgenes enhanced tumorigenesis. In a mouse model of Carney complex tumor syndrome, a disease involving multiple endocrine and non-endocrine neoplasms, heterozygous knockout of the R1A regulatory subunit of protein kinase A led to papillary thyroid carcinoma development in 5 out of 44 mice.38

Tg-TRK-T1

TRbPV/PV

More than 50% of transgenic mice of the B6C3F1 strain with thyroid-targeted TRK-T1 tyrosine kinase expression developed follicular cell hyperplasia, which often progressed to papillary thyroid carcinomas in animals over 7 months of age.70 While tumors were composed of the papillae found in the human tumor, they lacked the classic nuclear clearing typical of papillary carcinomas. Few thyroid tumors in TRK-T1 mice developed the less-differentiated solid regions, and none of the tumors metastasized. It is likely that while TRK-T1 predisposed mice to develop papillary thyroid carcinomas, additional genetic mutations were required for transformation based upon the variability of tumor formation even within the same founder line.

A genetically engineered mouse model of follicular thyroid carcinoma was created by introduction of a dominant-negative mutation, named PV for the patient first identified with the mutation, into the thyroid hormone receptor b (TRb) locus by homologous recombination in a 129/Sv 3 C57BL/ 6J background strain.35 The PV mutation results in loss of TRb binding ability to active T3 hormone, abolishing transcriptional activation. The lack of negative feedback by T3 on the hypothalamus and pituitary gland led to persistent upregulation of TSH and follicular cell hyperplasia in these mice, which often caused dyspnea due to tracheal compression.82 TRbPV/PV homozygotes developed follicular cell hyperplasia by 3 weeks of age and invasive follicular thyroid carcinomas by 4– 5 months of age. Hematogenous metastases to the lungs and heart were noted in the majority of mice over 5 months of age, and the metastases often had foci of anaplasia consisting of spindle-shaped cells. A similar phenotype was evident when TRbPV/2 mice were created by cross-breeding TRbPV/PV mice with TRb knockout mice (Figs. 7–9).36 While this mouse model offers a reasonably good recapitulation of human follicular carcinoma arising from hyperplastic goiter, it differs in that these mice have elevated circulating T3 and T4 levels due to production by the tumor cells, while human follicular thyroid carcinomas are infrequently functional.17

Tg-c-Ha-ras

Transgenic mice expressing thyroid-targeted cHa-ras had a predisposition to developing papillary thyroid carcinomas.23,69 Two founder mice developed the disease at 10–12 months of age but did not transmit the transgene to offspring. A third founder mouse and 90% of progeny developed follicular cell hyperplasia, but not neoplasia. The fourth founder, which carried 20–30 copies of the ras transgene, developed papillary thyroid carcinoma with lung metastases at 9 months of age, although a thyroid origin of the lung tumors was not definitively established. When this founder, a C57BL/6J.DBA/2J strain, was backcrossed with DBA2J mice, all of the offspring had thyroid dysgenesis and early lethality. Backcrossing with C57BL/6J mice resulted in a normal phenotype. Thus, while the founder mice demonstrated papillary thyroid carcinomas, this phenotype could not be maintained in further generations. Other models

Tumors with pathologic features of papillary thyroid carcinoma have been described in transgenic mice expressing thyroid-targeted human papillomavirus type 16 E7 oncogene, which inhibits

Mouse Models of Follicular Thyroid Carcinoma

Tg-Rap1bG12V

Transgenic mice overexpressing a constitutively active form of Rap1 that lacks GTPase activity, Rap1bG12V, developed follicular cell hyperplasia and adenomas within 6 months of goitrogen (methimazole and perchlorate) treatment and follicular carcinomas after 1 year.66 Hyperplasia and adenomas were reversible upon 2 months of goitrogen removal provided that progression to carcinoma was absent, indicating that the early adenomas were not truly autonomous. While follicular carcinomas were locally invasive into

6

Knostman, Jhiang, and Capen

Vet Pathol 44:1, 2007

Table 2. Comparison of human thyroid tumors and genetically engineered mouse models of thyroid cancer with similar genetic mutations. Tumor Morphology*

Genetic Alteration

Human

Mouse

Ret/PTC1

Typical PTC

Typical PTC

Ret/PTC3

Typical to solid PTC

Typical to solid PTC

BRAFV600E

Tall cell variant or typical PTC with necrosis and anaplasia

Tall cell variant or typical PTC with foci of anaplasia

TRK

Typical PTC

ras

FTC or follicular variant PTC

PTC with absence of characteristic nuclear abnormalities Typical PTC

p53 ATC inactivation/ loss

Ret

MTC

Biologic Behavior Human

Frequent local invasion, regional lymph node and less common distant metastases Frequent local invasion, regional lymph node and less common distant metastases Very frequent local invasion and anaplasia; loss of differentiation markers Local invasion, regional lymph node and less common distant metastases Local invasion, regional lymph node and/or hematogenous metastases Rapid local invasion and metastases with loss of differentiation markers

Mouse

Local invasion without any metastasis Local invasion with rare lymph node metastases Local invasion and anaplasia; maintenance of thyroglobulin expression Invasion not reported; absence of metastases Local invasion with rare lung metastases

Increased anaplasia, Local invasion with rare invasion and metastases and early metastases in Ret/ death PTC models of PTC (p53 not examined alone) MTC +/2 PTC C-cell hyperplasia C-cell hyperplasia progressing to MTC{; progressing to MTC; distant spread common in very rare metastases; advanced disease; tumors tumors produce produce calcitonin calcitonin

* PTC 5 papillary thyroid carcinoma; FTC 5 follicular thyroid carcinoma; ATC 5 anaplastic thyroid carcinoma; MTC 5 medullary thyroid carcinoma. { NR 5 not reported. { hereditary cases (e.g., MEN 2A).

the thyroid capsule, local blood vessels and perithyroidal soft-tissue metastases were not detected. The constitutively active Rap1bG12V cassette used to create this mouse model was floxed and followed by a dominant negative Rap1bS17N such that upon cross-breeding with a tamoxifeninducible Cre mouse and administration of tamoxifen, the constitutively active Rap1bG12V was removed and the dominant negative Rap1bS17N was expressed in its place. When the Rap1b ‘‘switch’’ was made from constitutively active Rap1bG12V to dominant negative Rap1bS17N, thyroid gland size was reduced by 50% in the face of continued goitrogen treatment. Ki67, BrdU, and PCNA labeling indices and terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling

indicated that decreased cellular proliferation, rather than increased apoptosis, accounted for the decrease in thyroid hyperplasia. This study suggests an important role for Rap1b in TSH-induced thyroid hyperplasia and tumorigenesis. Other models

Follicular thyroid carcinomas have been described in mice expressing a mutated form of the a1B adrenergic receptor under the control of the Tg promoter, which leads to upregulated cAMP and IP3-Ca++ signaling in the thyroid gland.15,48,49 Tgki-ras transgenic mice also developed well-differentiated follicular thyroid carcinomas at a low rate with long latency upon treatment with TSH or goitrogens, suggesting that while ras mutation

Mouse Models of Thyroid Cancer

Vet Pathol 44:1, 2007

Table 2.

Extended

Hormonal Derangement Human

None typical

Mouse

Hypothyroidism

None typical

NR{

None typical

High TSH euthyroid

None typical

None

None typical

None

None typical

Hypothyroidism (in combination with Ret/ PTC transgene expression)

Hypercalcitonism

Hypercalcitonism

alone is not sufficient to induce follicular thyroid carcinomas, it acts as a predisposing factor.12 Mouse Models of Anaplastic Thyroid Carcinoma Tg-SV40 LT

Anaplastic thyroid carcinomas developed in transgenic mice expressing thyroid-targeted Simian virus 40 large T antigen on a C57B/6J 3 DBA/2J background, which is the only published transgenic mouse model of this type of thyroid cancer.46 Mice were profoundly hypothyroid and required T4 supplementation in order to survive to an age where they could reproduce. By the age of 4– 6 weeks and as early as 9 days of age, most mice developed solid, anaplastic carcinomas with hemorrhage, necrosis, and few, if any, residual thyroid

7

follicles. A few mice survived long enough to develop lung metastases, while invasion of the trachea led to dyspnea and death in 90% of the transgenic mice by 22 weeks of age. Mouse Models of Medullary Thyroid Carcinoma CGRP-RetC634R

It is well known that in humans, point mutation of the ret proto-oncogene can lead to constitutive activation in neuroendocrine cells, such as thyroid C cells, leading to medullary thyroid carcinoma and/or the MEN syndromes. In transgenic mice expressing Ret with the common MEN 2A point mutation C634R under the control of the C cell– specific CGRP promoter, nearly all of the transgenic mice in all 3 founder lines developed early C cell hyperplasia with progression to bilateral medullary thyroid carcinomas by 8–12 months of age and rare systemic metastases (Figs. 10–12).52 Circulating calcitonin levels were elevated, indicating that these tumors were functional. Overexpression of wild-type Ret did not result in C-cell tumorigenesis.66 In one study, mice from a single CGRP-RetC634R founder line surprisingly developed papillary carcinomas, which were interpreted as evidence that activated Ret can transform thyroid follicular cells in addition to C cells.65 The development of papillary carcinoma is likely an artifact of transgene leakiness in follicular cells due to the specific chromosomal integration site in this founder line, since the CGRP promoter should target transgene expression to neuroendocrine and neural cells. There was marked variation in tumor penetrance between mouse background strains in a study using the CGRP-RetC634R model of medullary carcinoma, with tumors in 0% of FVB/ N mice, 14% of BALB/c mice, 64% of C67BL/6J mice, and 98% of CBA/ca mice all backcrossed from a single transgenic founder.19 Tumor size positively correlated with the degree of penetrance. This study highlights the role of modifier genes in disease phenotype and the need for careful consideration during selection of mouse background strains in a study, particularly when the resultant phenotype is unexpected. Rb and p53 deletional mutation

Approximately 40% of mice with simultaneous heterozygous deletional mutation of Rb and p53 (Rb+/2 3 p53+/2) on a 129 strain background developed C-cell hyperplasia and medullary thyroid carcinomas at approximately 7 months of age.29 Tumors were generally well differentiated and nonmetastatic. Interestingly, in one recent study using an Rb+/2 model with normal p53 status on a 129/Sv 3 C57BL/6 background, 56% of

8

Knostman, Jhiang, and Capen

Vet Pathol 44:1, 2007

Fig. 1. Thyroid gland; Ret/PTC1 transgenic mouse. Well-demarcated bilateral papillary thyroid carcinomas are present. Remaining non-neoplastic thyroid gland has large, quiescent follicles due to dietary L-thyroxine supplementation. HE; Bar 5 1 mm. Tissue courtesy of Dr. Je-Yoel Cho.

Vet Pathol 44:1, 2007

Mouse Models of Thyroid Cancer

mice developed medullary thyroid carcinomas, and there were rare metastases to liver, lung, lymph node, and adrenal gland.96 Thus, loss of 1 allele of Rb was sufficient to predispose mice to medullary thyroid carcinomas, depending on the background strain. Naturally, Rb+/2 and p53+/2 mice also developed many nonthyroidal neoplasms and had shortened life spans. Spontaneous activating mutations of Ret were detected in 4 out of 8 medullary thyroid carcinomas from Rb+/2 3 p53+/2 mice.18 While Rb loss has been detected immunohistochemically in human thyroid malignancies of many types,1 its precise role is unclear in the development of spontaneous medullary thyroid carcinoma in humans.

9

CGRP-v-Ha-ras

Transgenic mice of a C57BL/6 3 SJL strain expressing v-Ha-ras in C cells under control of the CGRP promoter developed C-cell hyperplasia progressing to medullary thyroid carcinoma in 85%–93% of animals (depending on founder line) between the ages of 6–12 months.34 Tumors were functional in secreting calcitonin, as is common in the human disease. Metastasis occurred rarely to the lungs and cervical lymph nodes. Some tumors had amyloid deposition, cystic cavitation, and vascular invasion and hemorrhage, characteristic features of human medullary thyroid carcinomas. Ras mutations have not been detected in human

r Fig. 2. Thyroid gland; Ret/PTC1 transgenic mouse. Higher magnification of a well-differentiated papillary thyroid carcinoma, illustrating the fronds of neoplastic cells extending into colloid-filled follicles. HE; Bar 5 50 mm. Tissue courtesy of Dr. Je-Yoel Cho. Fig. 3. Thyroid gland; Ret/PTC1 transgenic mouse. High-magnification thin section of a papillary thyroid carcinoma demonstrating the nuclear invaginations (arrowheads) and ground-glass nuclei (inset) that are characteristic of the human tumor. HE; Bar 5 15 mm (inset: bar 5 3 mm). Photo reproduced from Jhiang et al: Endocrinology 137:375–378, 1996, with permission from The Endocrine Society. Fig. 4. Thyroid gland; Ret/PTC1 transgenic 3 p532/2 mouse. Bilateral papillary thyroid carcinomas of large size have replaced all normal thyroid tissue and invaded the adjacent trachea. HE; Bar 5 1 mm. Photo reprinted from La Perle et al: Am J Pathol 157:671–677, 2000, with permission from the American Society for Investigative Pathology. Fig. 5. Thyroid gland; Ret/PTC1 transgenic 3 p532/2 mouse. Higher magnification of a poorly differentiated papillary thyroid carcinoma with multiple mitotic figures. HE; Bar 5 50 mm. Photo reprinted from La Perle et al: Am J Pathol 157:671–677, 2000, with permission from the American Society for Investigative Pathology. Fig. 6. Liver; Ret/PTC1 transgenic 3 p532/2 mouse. Two metastatic papillary thyroid carcinomas are present within the hepatic parenchyma (lower). HE; Bar 5 1 mm. Positive immunostaining for thyroglobulin confirms the lesions as metastatic papillary thyroid carcinomas (inset). Chromagen DAB detection method with HE. Bar 5 50 mm. Photo reprinted from La Perle et al: Am J Pathol 157:671–677, 2000, with permission from the American Society for Investigative Pathology. Fig. 7. Thyroid gland; TRbPV/2 mouse. A follicular thyroid carcinoma invades the thyroid capsule (arrow). HE; Bar 5 50 mm. Photo reproduced from Kato et al: Endocrinology 145:4430–4438, 2004, with permission from the The Endocrine Society (courtesy of Dr. Sheue-yann Cheng). Fig. 8. Thyroid gland; TRbPV/2 mouse. Vascular invasion is characteristic of follicular thyroid carcinomas (arrow). HE; Bar 5 50 mm. Photo reproduced from Kato et al: Endocrinology 145:4430–4438, 2004, with permission from The Endocrine Society (courtesy of Dr. Sheue-yann Cheng). Fig. 9. Thyroid gland; TRbPV/2 mouse. Foci of anaplasia are noted in regions of follicular hyperplasia and carcinoma (arrow). HE; Bar 5 50 mm. Photo reproduced from Kato et al: Endocrinology 145:4430–4438, 2004, with permission from The Endocrine Society (courtesy of Dr. Sheue-yann Cheng). Fig. 10. Thyroid gland; CGRP-RetC634R transgenic mouse. A large, invasive C-cell carcinoma is present within the right lobe of the thyroid gland (arrow), while the opposite lobe contains a papillary thyroid carcinoma. HE; Bar 5 1 mm. Photo reprinted from Reynolds et al: Oncogene 20:3986–3994; 2001, with permission from Nature Publishing Group (courtesy of Dr. Aaron Cranston and Professor Bruce Ponder). Fig. 11. Thyroid gland; CGRP-RetC634R transgenic mouse. Higher magnification of a C-cell carcinoma reveals characteristic neuroendocrine packeting of neoplastic cells. Calcitonin immunostain with hematoxylin counterstain; Bar 5 500 mm. Photo reprinted from Reynolds et al: Oncogene 20:3986–3994; 2001, with permission from Nature Publishing Group (courtesy of Dr. Aaron Cranston and Professor Bruce Ponder). Fig. 12. Thyroid gland; CGRP-RetC634R transgenic mouse. High magnification of a C-cell carcinoma demonstrates the fine fibrovascular stroma dividing lobules of polyhedral neoplastic cells. Ret immunostain with hematoxylin counterstain; Bar 5 30 mm. Photo reprinted from Reynolds et al: Oncogene 20:3986–3994; 2001, with permission from Nature Publishing Group (courtesy of Dr. Aaron Cranston and Professor Bruce Ponder).

10

Knostman, Jhiang, and Capen

cases of medullary thyroid carcinoma. Thus, this mouse model offers a better phenotypic than genotypic representation of the human disease. Other models

All transgenic mice coexpressing a truncated form of the polyomavirus (Py) middle-T antigen and the full-length Py small-T antigen under control of a composed Py early promoter/enhancer developed medullary thyroid carcinomas by 3–7 months of age.22 Tumors did not metastasize, and the animals had an unexpected waviness of hair and whiskers due to disorganized hair follicles in the dermal layer. In one of the earliest mouse models of medullary carcinomas, transgenic mice carrying the c-mos proto-oncogene, under control of the Moloney murine sarcoma virus long-terminal repeat, developed a syndrome similar to MEN 2A, consisting of medullary carcinomas and adrenal medullary pheochromocytomas, after a long latency.75 In this model, like the CGRP-RetC634R model,19 tumors were more prevalent on a BALB/c background than an FVB/N background. The Future of Thyroid Cancer Research Using Genetically Engineered Mouse Models Transgenic mice expressing Ret/PTC1, Ret/ PTC3 Trk-T1, BRAF, or ras offer a reasonable approximation of the features of papillary thyroid carcinomas in humans. However, even with a p53 knockout, no model has been able to demonstrate significant tumor dedifferentiation or metastasis. One limitation has been the fact that p53 knockout mice develop extrathyroidal neoplasms at a high rate, resulting in a shortened life span. A tissuespecific p53 knockout would help to eliminate this problem and allow the mice to live long enough to potentially develop more advanced thyroid cancer. Follicular thyroid carcinoma has been primarily investigated using a single mouse model, TRbPV/PV. The limitation of this model is the presence of hyperthyroidism and thyroid hormone resistance, which is not typical of the human disease. Because follicular thyroid carcinomas are more common in areas of dietary iodide deficiency, it is interesting that chronic TSH stimulation in the TRbPV/PV mice resulted in this type of neoplasm. However, rodents are notoriously susceptible to thyroid neoplasia because of perturbations of the pituitary-thyroid axis.8,9 There currently is a paucity of genetically engineered mouse models of anaplastic thyroid carcinoma, although in mice, SCID xenograft models are abundant. As previously mentioned, few papillary and follicular thyroid carcinomas

Vet Pathol 44:1, 2007

undergo significant dedifferentiation in transgenic mouse models. The only published transgenic model of anaplastic carcinoma, Tg-SV40 LT, rapidly developed severe hypothyroidism and fatal thyroid tumors as a result of tracheal invasion. An inducible model would facilitate maintenance and breeding of these mice and would better reproduce anaplastic carcinoma in the adult animal, which is more typical in human disease. Many of the mouse models of thyroid follicular cell neoplasia fail to reproduce the normal hormonal milieu present in humans with thyroid cancer. For example, derangement of thyroid function in mouse models remains a problem. Rapid onset of dysplasia or neoplasia replacing the majority of the normal thyroid tissue, especially in neonatal and juvenile mice, often results in significant hypothyroidism unless thyroid hormone supplementation is instituted. In addition, human thyroid neoplasms are more than twofold more common in women than in men, suggesting that estrogen plays a role in tumorigenesis, while no sex predilection has been achieved in the current mouse models. Reproduction of the MEN 2A syndrome using CGRP-RetC634R has been quite successful. However, in this model, as well as the Rb+/2 models, there appears to be a significant contribution of background strain to the development of medullary thyroid carcinomas. In addition, these models develop several extrathyroidal neoplasms common to the MEN 2A syndrome, while only the CGRP-vHa-ras model mimics the presence of medullary thyroid carcinoma alone, which is the most common form of the disease in humans. Overall, there is a need for the development of inducible mouse models of thyroid cancer. All of the available mouse models have genetic mutations from the earliest stages of development onward, while many naturally occurring human cases of thyroid cancer result from somatic mutations during childhood or beyond. Additionally, little research has been performed to test novel therapies in vivo. For example, while a great deal of recent research has focused upon signal transduction inhibitors directed toward Ret, ras, raf, and ERK in tumors of follicular and C-cell origin in vitro,91 these compounds have only been tested in a few SCID mouse xenograft models of thyroid cancer. Pharmacologic therapeutic intervention using genetically engineered mouse models of thyroid cancer would provide more useful information as to the feasibility, efficacy, and safety of signal transduction inhibitors in a relatively realistic in vivo setting. The continually increasing incidence

Mouse Models of Thyroid Cancer

Vet Pathol 44:1, 2007

of thyroid cancer in humans and lack of successful treatment options for dedifferentiated, invasive, or metastatic lesions makes mouse models invaluable in future therapeutic investigations.

12

Acknowledgement We would like to thank Tim Vojt in the Ohio State University College of Veterinary Medicine for technical assistance with figure preparation. This work was generously supported by Schering-Plough Research Institute.

13

References 1 Anwar F, Emond MJ, Schmidt RA, Hwang HC, Bronner MP: Retinoblastoma expression in thyroid neoplasms. Mod Pathol 13:562–569, 2000 2 Bankert RB, Hess SD, Egilmez NK: SCID mouse models to study human cancer pathogenesis and approaches to therapy: potential, limitations, and future directions. Front Biosci 7:c44–62, 2002 3 Bauer AJ, Terrell R, Doniparthi NK, Patel A, Tuttle RM, Saji M, Ringel MD, Francis GL: Vascular endothelial growth factor monoclonal antibody inhibits growth of anaplastic thyroid cancer xenografts in nude mice. Thyroid 12:953–961, 2002 4 Behe M, Kluge G, Becker W, Gotthardt M, Behr TM: Use of polyglutamic acids to reduce uptake of radiometal-labeled minigastrin in the kidneys. J Nucl Med 46:1012–1015, 2005 5 Black HE, Capen CC, Young DM: Ultimobranchial thyroid neoplasms in bulls: a syndrome resembling medullary thyroid carcinoma in man. Cancer 32:865–878, 1973 6 Boice JD Jr: Radiation-induced thyroid cancer: what’s new? J Natl Cancer Inst 97:703–705, 2005 7 Buckwalter TLF, Venkateswaran A, Lavender M, La Perle KMD, Cho J-Y, Robinson ML, Jhiang SM: The roles of phosphotyrosines-294, -404, and -451 in RET/PTC1-induced thyroid tumor formation. Oncogene 21:8166–8172, 2002 8 Capen CC: Mechanistic data and risk assessment of selected toxic end points of the thyroid gland. Toxicol Pathol 25:39–48, 1997 9 Capen CC: Overview of structural and functional lesions in endocrine organs in animals. Toxicol Pathol 29:8–33, 2001 10 Cardis E, Kesminiene A, Ivanov V, Malakhova I, Shibata Y, Khrouch V, Drozdovitch V, Maceika E, Zvonova I, Vlassov O, Bouville A, Goulko G, Hoshi M, Abrosimov A, Anoshko J, Astakhova L, Chekin S, Demidchik E, Galanti R, Ito M, Korobova E, Lushnikov E, Maksioutov M, Masyakin V, Nerovnia A, Parshin V, Parshkov E, Piliptsevich N, Pinchera A, Polyakov S, Shabeka N, Suonio E, Tenet V, Tsyb A, Yamashita S, Williams D: Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst 97:724–732, 2005 11 Chang JW, Yeh KY, Shen YC, Hsieh JJ, Chuang CK, Liao SK, Tsai LH, Wang CH: Production of

14

15

16

17 18

19

20

21

22

11

multiple cytokines and induction of cachexia in athymic nude mice by a new anaplastic thyroid carcinoma cell line. J Endocrinol 179:387–394, 2003 Chiappetta G, Fabien N, Picone A, Califano D, Monaco C, de Franciscis V, Vecchio G, Santelli G: Transgenic mice carrying the human KRAS oncogene under the control of a thyroglobulin promoter: KRAS expression in thyroids analyzed by in situ hybridization. Oncol Res 8:85–93, 1996 Cho J-Y, Sagartz JE, Capen CC, Mazzaferri EL, Jhiang SM: Early cellular abnormalities induced by Ret/PTC1 oncogene in thyroid-targeted transgenic mice. Oncogene 18:3659–3665, 1999 Coppe´e F, Depoortere F, Bartek J, Ledent C, Parmentier M, Dumont JE: Differential patterns of cell cycle regulatory proteins expression in transgenic models of thyroid tumors. Oncogene 17:631–41, 1998 Coppe´e F, Ge´rard A-C, Denef J-F, Ledent C, Vassart G, Dumont JE, Parmentier M: Early occurrence of metastatic differentiated thyroid carcinomas in transgenic mice expressing the A2a adenosine receptor gene and the human papillomavirus type 16 E7 oncogene. Oncogene 13:1471–1482, 1996 Corsetti F, Chianelli M, Cornelissen B, Van de Wiele C, D’Alessandria C, Slegers G, Mather SJ, Di Mario U, Filetti S, Scopinaro F, Signore A: Radioiodinated recombinant human TSH: a novel radiopharmaceutical for thyroid cancer metastases detection. Cancer Biother Radiopharm 19:57–63, 2004 Cotran RS, Kumar V, Collins T: Robbins Pathologic Basis of Disease, 6th ed., pp. 1142–1147. W. B. Saunders Company, Philadelphia, PA, USA, 1999. Coxon AB, Ward JM, Geradts J, Otterson GA, Zajac-Kaye M, Kaye FJ: RET cooperates with RB/ p53 inactivation in a somatic multi-step model for murine thyroid cancer. Oncogene 17:1625–1628, 1998 Cranston AN, Ponder BAJ: Modulation of medullary thyroid carcinoma penetrance suggests the presence of modifier genes in a RET transgenic mouse model. Cancer Res 63:4777–4780, 2003 Dackiw AP, Ezzat S, Huang P, Liu W, Asa SL: Vitamin D3 administration induces nuclear p27 accumulation, restores differentiation, and reduces tumor burden in a mouse model of metastatic follicular thyroid cancer. Endocrinology 145:5840– 5846, 2004 Ezzat S, Huang P, Dackiw A, Asa SL: Dual inhibition of RET and FGFR4 restrains medullary thyroid cancer cell growth. Clin Cancer Res 11:1336–1341, 2005 Felici A, Giorgio M, Krauzewicz N, Della Rocca C, Santoro M, Rovere P, Manni I, Amati P, Pozzi L: Medullary thyroid carcinomas in transgenic mice expressing a Polyoma carboxyl-terminal truncated middle-T and wild type small-T antigens. Oncogene 18:2387–2395, 1999

12

Knostman, Jhiang, and Capen

23 Feunteun J, Michiels F, Rochefort P, Caillou B, Talbot M, Fournes B, Mercken L, Schlumberger M, Monier R: Targeted oncogenesis in the thyroid of transgenic mice. Horm Res 47:137–139, 1997 24 Gandolfi PP, Frisina A, Raffa M, Renda F, Rocchetti O, Ruggeri C, Tombolini A: The incidence of thyroid carcinoma in multinodular goiter: retrospective analysis. Acta Biomed Ateneo Parmense 75:114–117, 2004 25 Garcia-Rostan G, Tallini G, Herrero A, D’Aquila TG, Carcangiu ML, Rimm DL: Frequent mutation and nuclear localization of beta-catenin in anaplastic thyroid carcinoma. Cancer Res 59:1811–1815, 1999 26 Gerling MC, Jossart G, Duh QY, Weier HU, Clark OH, Young DM: Invasion of human follicular thyroid carcinoma cells in an in vivo invasion model. Thyroid 9:1221–1226, 1999 27 Gimm O, Dralle H: C-cell cancer-prevention and treatment. Langenbecks Arch Surg 384:16–23, 1999 28 Gyory F, Mezosi E, Szakall S, Bajnok L, Varga E, Borbely A, Gazdag A, Juhasz I, Lukacs G, Nagy EV: Establishment of the hu-PBL-SCID mouse model for the investigation of thyroid cancer. Exp Clin Endocrinol Diabetes 113:359–364, 2005 29 Harvey M, Vogel H, Lee EY, Bradley A, Donehower LA: Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res 55:1146–1151, 1995 30 Hosal SA, Apel RL, Freeman JL, Azadian A, Rosen IB, LiVolsi VA, Asa SL: Immunohistochemical localization of p53 in human thyroid neoplasms: correlation with biological behavior. Endocr Pathol 8:21–28, 1997 31 Iuliano R, Trapasso F, Le Pera I, Schepis F, Sama I, Clodomiro A, Dumon KR, Santoro M, Chiariotti L, Viglietto G, Fusco A: An adenovirus carrying the rat protein tyrosine phosphatase eta suppresses the growth of human thyroid carcinoma cell lines in vitro and in vivo. Cancer Res 63:882–886, 2003 32 Jacobson A, Salnikov A, Lammerts E, Roswall P, Sundberg C, Heldin P, Rubin K, Heldin NE: Hyaluronan content in experimental carcinoma is not correlated to interstitial fluid pressure. Biochem Biophys Res Commun 305:1017–1023, 2003 33 Jhiang SM, Sagartz JE, Tong Q, Parker-Thornburg J, Capen CC, Cho J-Y, Xing S, Ledent C: Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology 137:375– 378, 1996 34 Johnston D, Hatzis D, Sunday ME: Expression of vHa-ras driven by the calcitonin/calcitonin generelated peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma. Oncogene 16:167–177, 1998 35 Kaneshige M, Kaneshige K, Zhu X, Dace A, Garrett L, Carter TA, Kazlauskaite R, Pankratz DG, Wynshaw-Boris A, Refetoff S, Weintraub B, Willingham MC, Barlow C, Cheng S: Mice with a targeted mutation in the thyroid hormone beta receptor gene exhibit impaired growth and resistance

36

37

38

39

40

41

42 43

44

45

46

47

48

Vet Pathol 44:1, 2007

to thyroid hormone. Proc Natl Acad Sci USA 97:13209–13214, 2000 Kato Y, Ying H, Willingham MC, Cheng S-Y: A tumor-suppressor role for thyroid hormone b receptor in a mouse model of thyroid carcinogenesis. Endocrinology 145:4430–4438, 2004 Kim S, Park YW, Schiff BA, Doan DD, Yazici Y, Jasser SA, Younes M, Mandal M, Bekele BN, Myers JN: An orthotopic model of anaplastic thyroid carcinoma in athymic nude mice. Clin Cancer Res 11:1713–1721, 2005 Kirschner LS, Kusewitt DF, Matyakhina L, Towns WH 2nd, Carney JA, Westphal H, Stratakis CA: A mouse model of the Carney complex tumor syndrome develops neoplasia in cyclic AMP-responsive tissues. Cancer Res 65:4506–4514, 2005 Klugbauer S, Lengfelder E, Demidchik EP, Rabes HM: High prevalence of RET rearrangement in thyroid tumors of children from Belarus after the Chernobyl reactor accident. Oncogene 11:2459– 2467, 1995 Knauf JA, Ma X, Smith EP, Zhang L, Mitsutake N, Liao X-H, Refetoff S, Nikiforov YE, Fagin JA: Targeted expression of BRAFV600E in thyroid cells of transgenic mice results in papillary thyroid cancers that undergo dedifferentiation. Cancer Res 65:4238–4245, 2005 Kraeber-Bodere F, Sai-Maurel C, Campion L, Faivre-Chauvet A, Mirallie E, Cherel M, Supiot S, Barbet J, Chatal JF, Thedrez P: Enhanced antitumor activity of combined pretargeted radioimmunotherapy and paclitaxel in medullary thyroid cancer xenograft. Mol Cancer Ther 1:267–274, 2002 Kroll TG: Molecular events in follicular thyroid tumors. Cancer Treat Res 122:85–105, 2004 Lacroix L, Lazar V, Michiels S, Ripoche H, Dessen P, Talbot M, Caillou B, Levillain JP, Schlumberger M, Bidart JM: Follicular thyroid tumors with the PAX8-PPARgamma1 rearrangement display characteristic genetic alterations. Am J Pathol 167:223–231, 2005 LaPerle KMD, Jhiang SM, Capen CC: Loss of p53 promotes anaplasia and local invasion in ret/PTC1induced thyroid carcinomas. Am J Pathol 157:671–677, 2000 Lawal O, Agbakwuru A, Olayinka OS, Adelusola K: Thyroid malignancy in endemic nodular goitres: prevalence, pattern and treatment. Eur J Surg Oncol 27:157–61, 2001 Ledent C, Coppee F, Dumont JE, Vassart G, Parmentier M: Transgenic models for proliferative and hyperfunctional thyroid diseases. Exp Clin Endocrinol Diabetes 104 Suppl 3:43–46, 1996 Ledent C, Dumont J, Vassart G, Parmentier M: Thyroid adenocarcinomas secondary to tissue-specific expression of simian virus-40 large T antigen in transgenic mice. Endocrinology 129:1391–1401, 1991 Ledent C, Franc B, Parmentier M: Transgenic mouse models: their interest in thyroid tumors. Arch Anat Cytol Pathol 46:31–37, 1998

Vet Pathol 44:1, 2007

Mouse Models of Thyroid Cancer

49 Ledent C, Marcotte A, Dumont JE, Vassart G, Parmentier M: Differentiated carcinomas develop as a consequence of the thyroid-specific expression of a thyroglobulin-human papillomavirus type 16 E7 transgene. Oncogene 10:1789–1797, 1995 50 Mack WJ, Preston-Martin S, Bernstein L, Qian D, Xiang M: Reproductive and hormonal risk factors for thyroid cancer in Los Angeles County females. Cancer Epidemiol Biomarkers Prev 8:991–997, 1999 51 McGregor LM, McCune BK, Graff JR, McDowell PR, Romans KE, Yancopoulos GD, Ball DW, Baylin SB, Nelkin BD: Roles of trk family neurotrophin receptors in medullary thyroid carcinoma development and progression. Proc Natl Acad Sci USA 96:4540–4545, 1999 52 Michiels F-M, Chappuis S, Caillou B, Pasini A, Talbot M, Monier R, Lenoir GM, Feunteun J, Billaud M: Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple endocrine neoplasia type 2A mutation. Proc Natl Acad Sci USA 94:3330–3334, 1997 53 Nikiforov YE: RET/PTC rearrangement in thyroid tumors. Endocr Pathol 13:3–16, 2002 54 Nikiforov YE: Genetic alterations involved in the transition from well-differentiated to poorly differentiated and anaplastic thyroid carcinomas. Endocr Pathol 15:319–328, 2004 55 Nikiforova MN, Stringer JR, Blough R, Medvedovic M, Fagin JA, Nikiforov YE: Proximity of chromosomal loci that participate in radiationinduced rearrangements in human cells. Science 290:138–41, 2000 56 Okano K, Usa T, Ohtsuru A, Tsukazaki T, Miyazaki Y, Yonekura A, Namba H, Shindoh H, Yamashita S: Effect of 22-oxa-1,25-dihydroxyvitamin D3 on human thyroid cancer cell growth. Endocr J 46:243–252, 1999 57 Portella G, Pacelli R, Libertini S, Cella L, Vecchio G, Salvatore M, Fusco A: ONYX-015 enhances radiation-induced death of human anaplastic thyroid carcinoma cells. J Clin Endocrinol Metab 88:5027–5032, 2003 58 Powell DJ Jr, Russell J, Nibu K, Li G, Rhee E, Liao M, Goldstein M, Keane WM, Santoro M, Fusco A, Rothstein JL: The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. Cancer Res 58:5523–5528, 1998 59 Powell DJ Jr, Russell JP, Li G, Kuo BA, Fidanza V, Huebner K, Rothstein JL: Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p532/2 mice. Oncogene 20:3235–3246, 2001 60 Puxeddu E, Zhao G, Stringer JR, Medvedovic M, Moretti S, Fagin JA: Characterization of novel nonclonal intrachromosomal rearrangements between the H4 and PTEN genes (H4/PTEN) in human thyroid cell lines and papillary thyroid cancer specimens. Mutat Res 570:17–32, 2005

13

61 Quayle FJ, Moley JF: Medullary thyroid carcinoma: including MEN 2A and MEN 2B syndromes. J Surg Oncol 89:122–129, 2005 62 Quidville V, Segond N, Pidoux E, Cohen R, Jullienne A, Lausson S: Tumor growth inhibition by indomethacin in a mouse model of human medullary thyroid cancer: implication of cyclooxygenases and 15-hydroxyprostaglandin dehydrogenase. Endocrinology 145:2561–2571, 2004 63 Quiros RM, Ding HG, Gattuso P, Prinz RA, Xu X: Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer 103:2261–2268, 2005 64 Ramos-Vara JA, Miller MA, Johnson GC, Pace LW: Immunohistochemical detection of thyroid transcription factor-1, thyroglobulin, and calcitonin in canine normal, hyperplastic, and neoplastic thyroid gland. Vet Pathol 39:480–487, 2002 65 Reynolds L, Jones K, Winton DJ, Cranston A, Houghton C, Howard L, Ponder BAJ, Smith DP: Ccell and thyroid epithelial tumours and altered follicular development in transgenic mice expressing the long isoform of MEN 2A RET. Oncogene 20:3986–3994, 2001 66 Ribeiro-Neto F, Leon A, Urbani-Brocard, Lou L, Nyska A, Altschuler DL: cAMP-dependent oncogenic action of Rap1b in the thyroid gland. J Biol Chem 270:46868–46875, 2004 67 Rios A, Rodriguez JM, Canteras M, Galindo PJ, Balsalobre MD, Parrilla P: Risk factors for malignancy in multinodular goitres. Eur J Surg Oncol 30:58–62, 2004 68 Rivas M, Santisteban P: TSH-activated signaling pathways in thyroid tumorigenesis. Mol Cell Endocrinol 213:31–45, 2003 69 Rochefort P, Caillou B, Michiels F-M, Ledent C, Talbot M, Schlumberger M, Lavelle F, Monier R, Feunteun J: Thyroid pathologies in transgenic mice expressing a human activated Ras gene driven by a thyroglobulin promoter. Oncogene 12:111–118, 1996 70 Russell JP, Powell DJ, Cunnane M, Greco A, Portella G, Santoro M, Fusco A, Rothstein JL: The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium. Oncogene 19:5729–5735, 2000 71 Sagartz JE, Jhiang SM, Tong Q, Capen CC: Thyroid-stimulating hormone promotes growth of thyroid carcinomas in transgenic mice with targeted expression of the ret/PTC1 oncogene. Lab Invest 76:307–318, 1997 72 Salnikov AV, Roswall P, Sundberg C, Gardner H, Heldin NE, Rubin K: Inhibition of TGF-beta modulates macrophages and vessel maturation in parallel to a lowering of interstitial fluid pressure in experimental carcinoma. Lab Invest 85:512–521, 2005 73 Santoro M, Chiappetta G, Cerrato A, Salvatore D, Zhang L, Manzo G, Picone A, Portella G, Santelli

14

74

75

76 77 78

79

80

81

82

83 84

85

Knostman, Jhiang, and Capen

G, Vecchio G, Fusco A: Development of thyroid papillary carcinomas secondary to tissue-specific expression of the RET/PTC1 oncogene in transgenic mice. Oncogene 12:1821–1826, 1996 Schmutzler C, Hoang-Vu C, Ruger B, Kohrle J: Human thyroid carcinoma cell lines show different retinoic acid receptor repertoires and retinoid responses. Eur J Endocrinol 150:547–556, 2004 Schulz N, Propst F, Rosenberg MP, Linnoila RI, Paules RS, Kovatch R, Ogiso Y, Vande Woude GF: Pheochromocytomas and C-cell thyroid neoplasms in transgenic c-mos mice: a model for the human multiple endocrine neoplasia type 2 syndrome. Cancer Res 52:450–455, 1992 Sheils O: Molecular classification and biomarker discovery in papillary thyroid carcinoma. Expert Rev Mol Diagn 5:927–946, 2005 Sherman SI: Thyroid carcinoma. Lancet 361:501– 511, 2003 Shi Y, Parhar RS, Zou M, Baitei E, Kessie G, Farid NR, Alzahrani A, Al-Mohanna FA: Gene therapy of anaplastic thyroid carcinoma with a single-chain interleukin-12 fusion protein. Hum Gene Ther 14:1741–1751, 2003 Soh EY, Eigelberger MS, Kim KJ, Wong MG, Young DM, Clark OH, Duh QY: Neutralizing vascular endothelial growth factor activity inhibits thyroid cancer growth in vivo. Surgery 128:1059–1065, 2000 Stein R, Goldenberg DM: A humanized monoclonal antibody to carcinoembryonic antigen, labetuzumab, inhibits tumor growth and sensitizes human medullary thyroid cancer xenografts to dacarbazine chemotherapy. Mol Cancer Ther 3:1559–1564, 2004 Strock CJ, Park JI, Rosen DM, Ruggeri B, Denmeade SR, Ball DW, Nelkin BD: Activity of irinotecan and the tyrosine kinase inhibitor CEP-751 in medullary thyroid cancer. J Clin Endocrinol Metab 91:79–84, 2006 Suzuki H, Willingham MC, Cheng S-Y: Mice with a mutation in the thyroid hormone receptor b gene spontaneously develop thyroid carcinoma: a mouse model of thyroid carcinogenesis. Thyroid 12:963– 969, 2002 Tallini G: Molecular pathobiology of thyroid neoplasms. Endocr Pathol 13:271–288, 2002 Teng L, Specht MC, Barden CB, Fahey TJ 3rd: Antisense hTERT inhibits thyroid cancer cell growth. J Clin Endocrinol Metab 88:1362–1366, 2003 Truong T, Orsi L, Dubourdieu D, Rougier Y, Hemon D, Guenel P: Role of goiter and of menstrual and reproductive factors in thyroid cancer: a population-based case-control study in New Caledonia (South Pacific), a very high incidence area. Am J Epidemiol 161:1056–1065, 2005

Vet Pathol 44:1, 2007

86 Vasko V, Ferrand M, Di Cristofaro J, Carayon P, Henry JF, de Micco C: Specific pattern of RAS oncogene mutations in follicular thyroid tumors. J Clin Endocrinol Metab 88:2745–2752, 2003 87 Viaggi M, Dagrosa MA, Belli C, Larripa I, Gangitano D, Cabrini R, Pisarev MA, Juvenal G: A new animal model for human undifferentiated thyroid carcinoma. Thyroid 13:529–536, 2003 88 Wang SH, Mezosi E, Wolf JM, Cao Z, Utsugi S, Gauger PG, Doherty GM, Baker JR Jr: IFNgamma sensitization to TRAIL-induced apoptosis in human thyroid carcinoma cells by upregulating Bak expression. Oncogene 23:928–935, 2004 89 Ward JM, Ohshima M: The role of iodine in carcinogenesis. Adv Exp Med Biol 206:529–542, 1986 90 Williams ED, Abrosimov A, Bogdanova T, Demidchik EP, Ito M, LiVolsi V, Lushnikov E, Rosai J, Sidorov Y, Tronko MD, Tsyb AF, Vowler SL, Thomas GA: Thyroid carcinoma after Chernobyl latent period, morphology and aggressiveness. Br J Cancer 90:2219–2224, 2004 91 Williams SF, Smallridge RC: Targeting the ERK pathway: novel therapeutics for thyroid cancer. Curr Drug Targets Immune Endocr Metabol Disord 4:199–220, 2004 92 Xing M: BRAF mutation in thyroid cancer. Endocr Relat Cancer 12:245–262, 2005 93 Yamazaki M, Straus FH, Messina M, Robinson BG, Takeda T, Hashizume K, DeGroot LJ: Adenovirusmediated tumor-specific combined gene therapy using Herpes simplex virus thymidine/ganciclovir system and murine interleukin-12 induces effective antitumor activity against medullary thyroid carcinoma. Cancer Gene Ther 11:8–15, 2004 94 Yeung SC, Xu G, Pan J, Christgen M, Bamiagis A: Manumycin enhances the cytotoxic effect of paclitaxel on anaplastic thyroid carcinoma cells. Cancer Res 60:650–656, 2000 95 Younes MN, Kim S, Yigitbasi OG, Mandal M, Jasser SA, Dakak Yazici Y, Schiff BA, El-Naggar A, Bekele BN, Mills GB, Myers JN: Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. Mol Cancer Ther 4:1146–1156, 2005 96 Ziebold U, Lee EY, Bronson RT, Lees JA: E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. Mol Cell Biol 23:6542–6552, 2003 97 Zou M, Famulski KS, Parhar RS, Baitei E, AlMohanna FA, Farid NR, Shi Y: Microarray analysis of metastasis-associated gene expression profiling in a murine model of thyroid carcinoma pulmonary metastasis: identification of S100A4 (Mts1) gene overexpression as a poor prognostic marker for thyroid carcinoma. J Clin Endocrinol Metab 89:6146–6154, 2004

Request reprints from Dr. Charles C. Capen, Department of Veterinary Biosciences, Ohio State University, 1925 Coffey Road, Columbus, Ohio 43210. E-mail: [email protected]

Suggest Documents