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Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAFV600E or wild-type BRAF

Oncogene volume 33, pages 5397–5404 (2014)Cite this article

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Abstract

Molecular signature of advanced and metastatic thyroid carcinoma involves deregulation of multiple fundamental pathways activated in the tumor microenvironment. They include BRAFV600E and AKT that affect tumor initiation, progression and metastasis. Human thyroid cancer orthotopic mouse models are based on human cell lines that generally harbor genetic alterations found in human thyroid cancers. They can reproduce in vivo and in situ (into the thyroid) many features of aggressive and refractory human advanced thyroid carcinomas, including local invasion and metastasis. Humanized orthotopic mouse models seem to be ideal and commonly used for preclinical and translational studies of compounds and therapies not only because they may mimic key aspects of human diseases (e.g. metastasis), but also for their reproducibility. In addition, they might provide the possibility to evaluate systemic effects of treatments. So far, human thyroid cancer in vivo models were mainly used to test single compounds, non selective and selective. Despite the greater antitumor activity and lower toxicity obtained with different selective drugs in respect to non-selective ones, most of them are only able to delay disease progression, which ultimately could restart with similar aggressive behavior. Aggressive thyroid tumors (for example, anaplastic or poorly differentiated thyroid carcinoma) carry several complex genetic alterations that are likely cooperating to promote disease progression and might confer resistance to single-compound approaches. Orthotopic models of human thyroid cancer also hold the potential to be good models for testing novel combinatorial therapies. In this article, we will summarize results on preclinical testing of selective and nonselective single compounds in orthotopic mouse models based on validated human thyroid cancer cell lines harboring the BRAFV600E mutation or with wild-type BRAF. Furthermore, we will discuss the potential use of this model also for combinatorial approaches, which are expected to take place in the upcoming human thyroid cancer basic and clinical research.

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Acknowledgements

This work was supported by the National Institutes of Health Grants NIHR21CA165039-01A1 and the American Thyroid Association funds for Thyroid Cancer Research to Carmelo Nucera (Principal Investigator: Human Thyroid Cancers Preclinical and Translational Research). Carmelo Nucera was also a recipient of the Guido Berlucchi research award (Brescia, Italy). Zeus A Antonello was a Masters Student at the BIDMC and is currently a PhD Student at the Instituto de Neurociencias (Alicante, Spain). We thank Mark Duquette and Neal Smith (BIDMC, Harvard Medical School) for critical reading of our manuscript. We thank those authors who we have neglected to cite owing to limitation on the number of references.

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  1. Experimental Division of Cancer Biology and Angiogenesis, Department of Pathology, Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Beth Israel Deaconess Medical Center, Simon C Fireman Research Center, Harvard Medical School, Boston, MA, USA

    Z A Antonello & C Nucera

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  1. Z A Antonello
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  2. C Nucera
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Correspondence to C Nucera.

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Antonello, Z., Nucera, C. Orthotopic mouse models for the preclinical and translational study of targeted therapies against metastatic human thyroid carcinoma with BRAFV600E or wild-type BRAF. Oncogene 33, 5397–5404 (2014). https://doi.org/10.1038/onc.2013.544

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  • DOI: https://doi.org/10.1038/onc.2013.544

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