Modeling Anaplastic Thyroid Carcinoma in the Mouse

Champa, Devora; Cristofano, Antonio Di

doi:10.1007/s12672-014-0208-8

Cited by 7 publications

(8 citation statements)

References 64 publications

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“…Deletion of Pten alone (or even with p53) does not appear to be sufficient in inducing medullary thyroid carcinoma. This is in contrast to the development of anaplastic thyroid tumors in Pten/p53-deficient mice (35,36) and highlights a central role of Rb in medullary thyroid tumor development.…”

Section: Selective Inactivation Of Tumor Suppressors P53 and Rb In mentioning

confidence: 65%

Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma

Song

Lin

Yao

et al. 2017

Journal of Biological Chemistry

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Among the four different types of thyroid cancer, treatment of medullary thyroid carcinoma poses a major challenge because of its propensity of early metastasis. To further investigate the molecular mechanisms of medullary thyroid carcinoma and discover candidates for targeted therapies, we developed a new mouse model of medullary thyroid carcinoma based on our mouse line. This system enables gene manipulation in parafollicular C cells in the thyroid, the purported cells of origin of medullary thyroid carcinoma. Selective inactivation of tumor suppressors, such as, , and, in mature parafollicular C cells via an inducible Cre recombinase from led to development of murine medullary thyroid carcinoma. Loss of accelerated /-induced medullary thyroid carcinoma, indicating interactions between pathways controlled by tumor suppressors. Moreover, labeling differentiated parafollicular C cells by allows us to follow their fate during malignant transformation to medullary thyroid tumor. Our findings support a model in which mutational events in differentiated parafollicular C cells result in medullary thyroid carcinoma. Through expression analysis including RNA-Seq, we uncovered major signaling pathways and networks that are perturbed following the removal of tumor suppressors. Taken together, these studies not only increase our molecular understanding of medullary thyroid carcinoma but also offer new candidates for designing targeted therapies or other treatment modalities.

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Section: Selective Inactivation Of Tumor Suppressors P53 and Rb In mentioning

confidence: 65%

Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma

Song

Lin

Yao

et al. 2017

Journal of Biological Chemistry

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“…ATC is typically accompanied by cell proliferation and chromosomal instability, and morphological features including the gradual loss of papillary and follicular growth patterns, biphasic spindle, solid growth squamoid pattern, areas of necrosis and hemorrhage, and nuclear pleomorphism (Parenti, Salvatorelli and Magro, 2014, Salvatore, Nappi, Salerno et al, 2007). The two common signaling pathways have been implicated in ATC are PI3K and MAPK (Champa and Di Cristofano, 2015). Differentiated thyroid cancers often have mutations in these pathways and undifferentiated thyroid cancer has additional mutations such as p53.…”

Section: Mouse Models For Anaplastic Thyroid Cancermentioning

confidence: 99%

“…It is well known that losing p53 protein alone is not sufficient to induce malignancy in the thyroid (Russo, Antico Arciuch and Di Cristofano, 2011). Earlier models of ATC were generated using transgenic mice expressing somatic rearrangements of the RET proto-oncogene ( RET-PTC1) (Champa and Di Cristofano, 2015, La Perle, Jhiang and Capen, 2000). The RET proto-oncogene encodes a transmembrane glycoprotein belonging to the receptor tyrosine kinase family.…”

Section: Mouse Models For Anaplastic Thyroid Cancermentioning

confidence: 99%

“…RET-PTC1 under thyroglobulin promoter in a p53 −/− background developed anaplastic-like tumors in a model by La Perle et al (La Perle et al, 2000). Although this model was useful, the mice developed extra-thyroidal tumors because of systemic deletion of p53 (Champa and Di Cristofano, 2015). Similar findings were made when RET-PTC3 transgenic mice were crossed into a p53 knockout background; interestingly, it was shown that aggressive tumors in this model eventually lost expression of the RET-PTC3 fusion protein, indicating that late stage progression did not require continued expression of the oncogene (Powell, Russell, Li et al, 2001).…”

Section: Mouse Models For Anaplastic Thyroid Cancermentioning

confidence: 99%

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Mouse models of thyroid cancer: A 2015 update

Kirschner

Qamri

Kari

et al. 2016

Molecular and Cellular Endocrinology

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Thyroid cancer is the most common endocrine neoplasm, and its rate is rising at an alarming pace. Thus, there is a compelling need to develop in vivo models which will not only enable the confirmation of the oncogenic potential of driver genes, but also point the way towards the development of new therapeutics. Over the past 20 years, techniques for the generation of mouse models of human diseases have progressed substantially, accompanied by parallel advances in the genetics and genomics of human tumors. This convergence has enabled the development of mouse lines carrying mutations in the genes that cause thyroid cancers of all subtypes, including differentiated papillary and follicular thyroid cancers, poorly differentiated/anaplastic cancers, and medullary thyroid cancers. In this review, we will discuss the state of the art of mouse modeling of thyroid cancer, with the eventual goal of providing insight into tumor biology and treatment.

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“…This has been deciphered through multiple genetically engineered mouse models that progress from follicular and papillary WDTC to undifferentiated ATC 1 . Currently, numerous transformations in molecular mechanisms governing the development of thyroid malignancy and subsequent progression into poorly differentiated and ATC have been identified.…”

Section: Common Genetic Anomalies In Atcmentioning

confidence: 99%

Targeting lipid metabolism for the treatment of anaplastic thyroid carcinoma

Roemeling¹,

Copland

2015

Expert Opinion on Therapeutic Targets

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Introduction Anaplastic thyroid carcinoma (ATC) is the rarest subtype of thyroid cancer, however it disproportionately accounts for a large percentage of all thyroid cancer related deaths and is considered one of the most lethal solid tumors in humans, having a median survival of only a few months upon diagnosis. While a variety of treatment options are available including surgery, radiation and targeted therapies, response rates are low, due in part to the drug-resistant nature of this disease; therefore, new avenues for therapeutic intervention are surely needed. Recent investigation into the metabolic profile of ATC has revealed a tumor-specific dependency for increased de novo lipogenesis, offering new insight into the molecular mechanisms that govern disease initiation and progression. Areas Covered Herein we summarize known oncogenic signaling pathways and current therapeutic strategies for the treatment of ATC. We further discuss the unique expression pattern of lipid metabolism constituents in this disease. Additionally, the current literature correlating aberrant lipogenesis with carcinogenesis is reviewed, and the implications of targeting this pathway as an innovative approach for treating ATC and other malignancies is discussed. As stearoyl-CoA desaturase (SCD) is the most differentially expressed constituent of lipid metabolism in ATC, an additional focus on this enzyme as a novel therapeutic target is applied. Expert Opinion This section is used to summarize the current research efforts underway in defining the role of lipid metabolism specifically in thyroid carcinoma. Included is a brief summary of lipid metabolism factors for which inhibitors have been generated and are under current investigation as anti-cancer agents. Finally, research limitations regarding the use of these inhibitors against components of this pathway are discussed.

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Modeling Anaplastic Thyroid Carcinoma in the Mouse

Cited by 7 publications

References 64 publications

Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma

Selective Ablation of Tumor Suppressors in Parafollicular C Cells Elicits Medullary Thyroid Carcinoma

Mouse models of thyroid cancer: A 2015 update

Targeting lipid metabolism for the treatment of anaplastic thyroid carcinoma

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