The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAF<sup>V600E</sup>-Positive Papillary and Anaplastic Thyroid Carcinoma

Borre, Pierre Vanden; McFadden, David G.; Gunda, Viswanath; Sadow, Peter M.; Varmeh, Shohreh; Bernasconi, Maria; Jacks, Tyler; Parangi, Sareh

doi:10.1089/thy.2013.0483

Cited by 33 publications

(40 citation statements)

References 31 publications

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“…Importantly, these models have also allowed for the study of cell lines with genetically-altered expression to interrogate pathways involved in thyroid cancer development and progression and explore their potential as therapeutic targets [36, 24, 44, 29, 4]. Finally, Parangi and colleagues have recently developed the next generation of orthotopic thyroid cancer models using immunocompetent mouse models, which will be valuable to study thyroid tumor biology and responses to therapy in the context of a functional immune system [43]. …”

Section: Discussionmentioning

confidence: 99%

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

et al. 2015

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Thyroid cancer incidence has been increasing over time, and it is estimated that ~1950 advanced thyroid cancer patients will die of their disease in 2015. To combat this disease, an enhanced understanding of thyroid cancer development and progression as well as the development of efficacious, targeted therapies are needed. In vitro and in vivo studies utilizing thyroid cancer cell lines and animal models are critically important to these research efforts. In this report, we detail our studies with a panel of authenticated human anaplastic and papillary thyroid cancer (ATC and PTC) cell lines engineered to express firefly luciferase in two in vivo murine cancer models- an orthotopic thyroid cancer model as well as an intracardiac injection metastasis model. In these models, primary tumor growth in the orthotopic model and the establishment and growth of metastases in the intracardiac injection model are followed in vivo using an IVIS imaging system. In the orthotopic model, the ATC cell lines 8505C and T238 and the PTC cell lines K1/GLAG-66 and BCPAP had take rates >90% with final tumor volumes ranging 84–214 mm3 over 4–5 weeks. In the intracardiac model, metastasis establishment was successful in the ATC cell lines HTh74, HTh7, 8505C, THJ-16T, and Cal62 with take rates ≥70%. Only one of the PTC cell lines tested (BCPAP) was successful in the intracardiac model with a take rate of 30%. These data will be beneficial to inform the choice of cell line and model system for the design of future thyroid cancer studies.

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Section: Discussionmentioning

confidence: 99%

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

et al. 2015

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“…For orthotopic implantation TBP-3743, were previously lentivirally transduced to produce cells expressing both luciferase and green fluorescent protein (GFP) [50]. The murine lines, along with the human ATC line, 8505c (Deutsche Sammlung von Mikrooranismen und Zellkulturen), and the human PTC line, BCPAP (previously provided by Dr. G. Damante of the University of Udine, Italy ) , were maintained in culture using Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and penicillin/streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Combined BRAFV600E- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer

et al. 2014

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Anaplastic (ATC) and refractory papillary thyroid cancer (PTC) lack effective treatments. Inhibition of either oncogenic BRAF or SRC has marked anti-tumor effects in mouse models of thyroid cancer, however, neither drug induces notable apoptosis. Here we report that the SRC-inhibitor dasatinib further sensitizes BRAFV600E-positive thyroid cancer cells to the BRAFV600E-inhibitor PLX4720. Combined treatment with PLX4720 and dasatinib synergistically inhibited proliferation and reduced migration in PTC and ATC cells. Whereas PLX4720 did not induce robust apoptosis in thyroid cancer cells, combined treatment with dasatinib induced apoptosis in 4 of 6 lines. In an immunocompetent orthotopic mouse model of ATC, combined PLX4720 and dasatinib treatment significantly reduced tumor volume relative to PLX4720 treatment alone. Immune cell infiltration was increased by PLX4720 treatment and this effect was maintained in mice treated with both PLX4720 and dasatinib. Further, combined treatment significantly increased caspase 3 cleavage in vivo relative to control or either treatment alone. In conclusion, combined PLX4720 and dasatinib treatment induces apoptosis, increases immune cell infiltration and reduces tumor volume in a preclinical model of ATC, suggesting that the combination of these FDA-approved drugs may have potential for the treatment of patients with ATC or refractory PTC.

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“…wileyonlinelibrary.com/journal/hed lines into immunodeficient mouse strains. 2,7,12 Immunodeficient models, however, fail to mimic the natural tumor microenvironment, because they do not evoke protective immune responses or tumorpromoting inflammation. 13 For this reason, genetically engineered strains have been developed to study tumors that arise in situ in immunocompetent hosts.…”

Section: Introductionmentioning

confidence: 99%

Structural alterations in tumor‐draining lymph nodes before papillary thyroid carcinoma metastasis

et al. 2017

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Background The purpose of this study was to define and characterize the thyroid tumor-draining lymph nodes in genetically engineered mice harboring thyroid-specific expression of oncogenic BrafV600E with and without Pten insufficiency. Methods After intratumoral injection of methylene blue, the lymphatic drainage of the thyroid gland was visualized in real time. The thyroid gland/tumor was resected en bloc with the respiratory system for histological analysis. Results Although mice harboring BrafV600E mutations were smaller in body size compared with their wild-type (WT) littermates, the size of their thyroid glands and deep cervical lymph nodes were significantly larger. Additionally, the tumor-draining lymph nodes showed increased and enlarged lymphatic sinuses that were distributed throughout the cortex and medulla. Tumor-reactive lymphadenopathy and histiocytosis, but no frank metastases, were observed in all mice harboring BrafV600E mutations. Conclusions The tumor-draining lymph nodes undergo significant structural alterations in immunocompetent mice, and this may represent a primer for papillary thyroid carcinoma (PTC) metastasis.

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The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAF^V600E-Positive Papillary and Anaplastic Thyroid Carcinoma

Cited by 33 publications

References 31 publications

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

Combined BRAFV600E- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer

Structural alterations in tumor‐draining lymph nodes before papillary thyroid carcinoma metastasis

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The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAFV600E-Positive Papillary and Anaplastic Thyroid Carcinoma

Cited by 33 publications

References 31 publications

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

Characterization of Thyroid Cancer Cell Lines in Murine Orthotopic and Intracardiac Metastasis Models

Combined BRAFV600E- and SRC-inhibition induces apoptosis, evokes an immune response and reduces tumor growth in an immunocompetent orthotopic mouse model of anaplastic thyroid cancer

Structural alterations in tumor‐draining lymph nodes before papillary thyroid carcinoma metastasis

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The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAF^V600E-Positive Papillary and Anaplastic Thyroid Carcinoma