Signaling pathways in follicular cell-derived thyroid carcinomas

Romitti, Mírian; Ceolin, Lucieli; Siqueira, Débora Rodrigues; Ferreira, Carla Vaz; Wajner, Simone Magagnin; Maia, Ana Luiza

doi:10.3892/ijo.2012.1681

Cited by 39 publications

(34 citation statements)

References 120 publications

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“…that lead to an aberrant and constitutive activation of MAPK pathway (Romitti et al 2013). BRAF V600E is an oncogenic protein with markedly elevated kinase activity that overactivates the MAPK pathway, especially ERK signaling transduction (Xing 2005, Chakravarty et al 2011.…”

Section: Discussionmentioning

confidence: 99%

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Romitti¹,

Wajner²,

Ceolin³

et al. 2016

Endocrine-Related Cancer

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Type 3 deiodinase (DIO3, D3) is reactivated in human neoplasias. Increased D3 levels in papillary thyroid carcinoma (PTC) have been associated with tumor size and metast atic disease. The objective of this study is to investigate the signaling pathways involved in DIO3 upregulation in PTC. Experiments were performed in human PTC cell lines (K1 and TPC-1 cells) or tumor samples. DIO3 mRNA and activity were evaluated by real-time PCR and ion-exchange column chromatography respectively. Western blot analysis was used to determine the levels of D3 protein. DIO3 gene silencing was performed via siRNA transfection. DIO3 mRNA levels and activity were readily detected in K1 (BRAF V600E ) and, at lower levels, in TPC-1 (RET/PTC1) cells (P!0.007 and PZ0.02 respectively). Similarly, DIO3 mRNA levels were higher in PTC samples harboring the BRAF V600E mutation as compared with those with RET/PTC1 rearrangement or negative for these mutations (P!0.001). Specific inhibition of BRAF oncogene (PLX4032, 3 mM), MEK (U0126, 10-20 mM) or p38 (SB203580, 10-20 mM) signaling was associated with decreases in DIO3 expression in K1 and TPC-1 cells. Additionally, the blockage of the sonic hedgehog (SHH) pathway by cyclopamine (10 mM) resulted in markedly decreases in DIO3 mRNA levels. Interestingly, siRNA-mediated DIO3 silencing induced decreases on cyclin D1 expression and partial G1 phase cell cycle arrest, thereby downregulating cell proliferation. In conclusion, sustained activation of the MAPK and SHH pathways modulate the levels of DIO3 expression in PTC. Importantly, DIO3 silencing was associated with decreases in cell proliferation, thus suggesting a D3 role in tumor growth and aggressiveness.

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Section: Discussionmentioning

confidence: 99%

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Romitti¹,

Wajner²,

Ceolin³

et al. 2016

Endocrine-Related Cancer

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“…The mechanism of MAPK activation differs in follicular-cell-derived tumours from medullary thyroid cancer. In follicularcell-derived tumours, for example, papillary thyroid cancer, BRAF mutations are often causative (23). In medullary thyroid cancer, MAPK activation is effectuated through the RET mutations (22).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients

Tiedje¹,

Ting

Walter

et al. 2016

European Journal of Endocrinology

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Objective: Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy. Design and methods: Clinical courses of 32 patients with sporadic MTC (n = 10 pN0cM0, n = 8 pN1cM0, n = 14 pN1cM1) were compared with genetic profiles of the patients' primary tumour tissue. Analysis for RET proto-oncogene mutations was performed by Sanger sequencing and next-generation sequencing (NGS). The mRNA expression (mRNA count) of 33 targets was measured by nCounter NanoString analysis. Results: Somatic RET mutations occurred in 21/32 patients. The RET918 mutation was found in 8/14 pN1cM1 patients. BRAF (P = 0.019), FGFR2 (P = 0.007), FGFR3 (P = 0.044) and VEGFC (P = 0.042) mRNA expression was significantly lower in pN1cM0/pN1cM1 compared with pN0cM0 patients, whereas PDGFRA (P = 0.026) mRNA expression was significantly higher in pN1cM0/pN1cM1 when compared with pN0cM0 patients. Among the 10/32 vandetanib-treated patients, 5 showed partial response (PR), all harbouring the RET918 mutation. mRNA expression of FLT1 (P = 0.039), FLT4 (P = 0.025) and VEGFB (P = 0.042) was significantly higher in therapy responders. Conclusions: In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastasis (both lymph node and organ metastasis) as well as response to vandetanib therapy.

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“…In recent years, molecular biological studies have revealed that the mutation of the genes BRAF and N-RAS is associated with anaplastic transformation (17,18), and conventional cancer chemotherapy has been shifting to molecular-targeted therapy.…”

Section: Discussionmentioning

confidence: 99%

Anaplastic Thyroid Carcinoma Treated with Lenvatinib

et al. 2017

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Anaplastic thyroid carcinoma (ATC), which accounts for 1%-2% of all malignant tumors of the thyroid, is known to be highly resistant to any therapy and has a 1-year survival rate of 5%-20% [1][2][3]. ATC patients are limited in number, and most die within 6 months after diagnosis, making it difficult to establish a standard treatment protocol. Multimodal therapy including surgery, radiotherapy and chemotherapy has been introduced, but survival times remain poor [4][5][6].The use of molecular-targeted drugs as cancer therapy has been rapidly increasing over the past decade. Lenvatinib, a new molecular-targeted anticancer drug, is a multi-targeted receptor tyrosine kinase inhibitor that inhibits the activities of vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet-derived growth factor receptors, KIT, and RET [7,8]. Lenvatinib exerts its anticancer activity via the suppression of tumor angiogenesis, and it is generally indicated for unresectable radioiodine-refractory differentiated thyroid cancers [9]. However, the evidence of the clinical effect of this drug on ATC is very limited. We herein report a case of ATC with local recur- Kurume Medical Journal, 64, 00-00, 2017 Summary: Objective: We report a case of anaplastic thyroid carcinoma (ATC) with local recurrence and distant metastasis that responded very well to treatment with lenvatinib, a new molecular-targeted anticancer drug. Case Report: A 91-year-old Japanese woman presented with a 5-month history of a painless mass in her left anterior neck. She had a past history of total thyroidectomy and neck dissection for papillary carcinoma of the thyroid. Here she underwent neck dissection, and the histopathological diagnosis was lymph node metastasis of papillary carcinoma with anaplastic transformation. Five months later, a cervical lymph node swelled up again.Computed tomography demonstrated an enhanced mass in the neck and multiple nodules in both lungs. Recurrent ATC with multiple lung metastases was diagnosed, and molecular-targeted therapy with lenvatinib was initiated. The neck tumor reduced in 1 week, and the pulmonary nodules became completely hollow within 1 month. However, we had to discontinue lenvatinib because of severe side effects including high blood pressure, hypocalcemia, and hypoalbuminemia. Soon after discontinuation, the side effects subsided, but the tumor rapidly regrew. The patient died of lymphangiosis carcinomatosa 6 days after discontinuation. Conclusion: Although recent advances in molecular-targeted therapy have provided powerful cancer therapy tools, the negative side of this therapy must be addressed.

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Signaling pathways in follicular cell-derived thyroid carcinomas

Cited by 39 publications

References 120 publications

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients

Anaplastic Thyroid Carcinoma Treated with Lenvatinib

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