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The most common thyroid malignancy is papillary thyroid cancer. While a majority respond to therapy and have a favorable prognosis, some papillary thyroid cancers persist. This subset may dedifferentiate to anaplastic thyroid cancer, an aggressive, highly invasive and rapidly fatal cancer. Thyroid cancer patients at risk for disease progression and metastasis need earlier, safer and more effective therapies. The purpose of this translational study was to determine if mebendazole could be repurposed to effectively treat thyroid cancer, in particular before metastasis. In vitro, mebendazole potently inhibited the growth of a panel of human papillary and anaplastic thyroid cancer cells. In papillary (B-CPAP) and anaplastic (8505c) cell lines, mebendazole increased the percentage of cells in G2/M cell cycle arrest and induced late stage apoptosis by activation of the caspase-3 pathway. In aggressive 8505c cells, mebendazole significantly repressed migratory and invasive potential in a wound healing and transwell invasion assay and inhibited expression of phosphorylated Akt and Stat3 and reduced Gli1. In vivo, mebendazole treatment resulted in significant orthotopic thyroid tumor regression (B-CPAP) and growth arrest (8505c), with treated tumors displaying reduced expression of the proliferation maker KI67 and less vascular epithelium as indicated by CD31+ immunohistochemistry. Most importantly, daily oral mebendazole prevented established thyroid tumors from metastasizing to the lung. Given the low toxicity and published anticancer mechanisms of mebendazole, this novel preclinical study of mebendazole in thyroid cancer has promising therapeutic implications for patients with treatment refractory papillary or anaplastic thyroid cancer.
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Molecular Mechanisms Unit, Nuclear Medicine Division, Scientific Directorate, Department of Experimental Oncology and Molecular Medicine
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Thyroid carcinomas derived from follicular cells comprise papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC) and undifferentiated anaplastic thyroid carcinoma (ATC). PTC, the most frequent thyroid carcinoma histotype, is associated with gene rearrangements that generate RET/PTC and TRK oncogenes and with BRAF-V600E and RAS gene mutations. These last two genetic lesions are also present in a fraction of PDTCs. The ERK1/2 pathway, downstream of the known oncogenes activated in PTC, has a central role in thyroid carcinogenesis. In this study, we demonstrate that the BRAF-V600E, RET/PTC, and TRK oncogenes upregulate the ERK1/2 pathway's attenuator cytoplasmic dual-phase phosphatase DUSP6/MKP3 in thyroid cells. We also show DUSP6 overexpression at the mRNA and protein levels in all the analysed PTC cell lines. Furthermore, DUSP6 mRNA was significantly higher in PTC and PDTC in comparison with normal thyroid tissues both in expression profile datasets and in patients' surgical samples analysed by real-time RT-PCR. Immunohistochemical and western blot analyses showed that DUSP6 was also overexpressed at the protein level in most PTC and PDTC surgical samples tested, but not in ATC, and revealed a positive correlation trend with ERK1/2 pathway activation. Finally, DUSP6 silencing reduced the neoplastic properties of four PTC cell lines, thus suggesting that DUSP6 may have a pro-tumorigenic role in thyroid carcinogenesis.
Department of Pathology, WRN219, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, 02114, USA
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Dear Editor, Patients with undifferentiated (anaplastic) thyroid carcinoma (ATC) are refractory to surgical treatment, chemotherapy, and/or radiotherapy, and have a dismal prognosis ( Smallridge et al . 2012 ). Distant metastasis occurs at various
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degradation . Oncogene 29 105 – 116 doi:10.1038/onc.2009.306 . Dahlman T Lammerts E Wik M Bergström D Grimelius L Westermark K Rubin K Heldin NE 2000 Fibrosis in undifferentiated (anaplastic) thyroid carcinomas: evidence for a dual
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gene expression in tissues of patients with FTC, PTC, and undifferentiated anaplastic thyroid carcinoma in comparison to control tissues of patients with goiter (mean 1.0; median 0.83; range 0.5–1.8) and tissue of normal thyroid (mean 1.09). As shown in
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different degrees of malignancy from benign adenomas, which are not invasive and very well differentiated, to the undifferentiated anaplastic thyroid carcinomas, which are very aggressive and always fatal. Papillary and follicular carcinomas, the most common
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thyroid carcinomas (PDTC) and undifferentiated anaplastic thyroid carcinomas (ATC) ( Sheils 2005 ). PTC accounts for ∼80% of all thyroid cancers; generally it is a slow-growing tumour type with a good prognosis, although rare, aggressive forms with local
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:10.1002/mc.20684 . Dahlman T Lammerts E Wik M Bergstrom D Grimelius L Westermark K Rubin K Heldin NE 2000 Fibrosis in undifferentiated (anaplastic) thyroid carcinomas: evidence for a dual action of tumour cells in collagen type I
Department of Pharmaco-Biology, Centro Sanitario, Department of Cellular Biology, Faculty of Pharmacy, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
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Department of Pharmaco-Biology, Centro Sanitario, Department of Cellular Biology, Faculty of Pharmacy, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
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Department of Pharmaco-Biology, Centro Sanitario, Department of Cellular Biology, Faculty of Pharmacy, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
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Department of Pharmaco-Biology, Centro Sanitario, Department of Cellular Biology, Faculty of Pharmacy, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
Department of Pharmaco-Biology, Centro Sanitario, Department of Cellular Biology, Faculty of Pharmacy, University of Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
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, Deng et al . 2006 ). In this report, we demonstrated that PPARγ acts as a tumor suppressor gene against two different human thyroid carcinoma cell lines. In both WRO, a well-differentiated thyroid follicular carcinoma and FRO, an undifferentiated/anaplastic
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Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, The Ohio State University, A438 Starling-Loving Hall, 320 West 10th Avenue, Columbus, Ohio 43210, USA
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carcinoma (DTC), undifferentiated (anaplastic) thyroid carcinoma (ATC), poorly DTC, and medullary thyroid carcinoma (MTC). DTCs are by far the most common, and include the major subtypes of papillary and follicular as well as rare tumors derived from these