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Targeting Epidermal Growth Factor Receptor 1 Signaling in Human Thyroid-Stimulating Hormone–Independent Thyroid Carcinoma FRO Cells Results in a More Chemosensitive and Less Angiogenic Phenotype

Targeting Epidermal Growth Factor Receptor 1 Signaling in Human Thyroid-Stimulating Hormone–Independent Thyroid Carcinoma FRO Cells Results in a More Chemosensitive and Less Angiogenic Phenotype

Abstract

Background: Poorly differentiated and anaplastic thyroid cancers are aggressive malignancies unresponsive to standard treatments. The mechanisms responsible for the progression of thyroid tumors toward a thyroid-stimulating hormone (TSH)–independent phenotype are still under discussion, and a better understanding of them may provide novel molecular targets for the treatment of this disease. We evaluated the hypothesis that epithelial growth factor (EGF) signaling may play a role in favoring the loss of TSH dependency in human differentiated thyroid tumor cells. Methods: The sensitivity to EGF stimulation was evaluated in follicular thyroid carcinoma WRO cells that retain some features of thyroid cell differentiation and in undifferentiated TSH-independent thyroid carcinoma FRO cells. Results: It was observed that, while both cell lines are characterized by a similar EGF-dependent activation of the RAS/MAPK signaling pathway, only FRO cells exhibited a significant induction of phosphoAKT, cell proliferation, and migration as well as the up-regulation of vascular endothelial growth factor-A expression in response to EGF. On the other hand, the inhibition of epidermal growth factor receptor 1 signaling by its tyrosine kinase inhibitor, erlotinib, caused a selective down-regulation of FRO cell proliferation and induced a phenotype more sensitive to the proapoptotic activity of anthracyclins and taxoids. By contrast, the protracted stimulation of TSH-dependent WRO cells with EGF induced the loss of TSH dependency and the rearrangement of F-actin cytoskeleton. Conclusions: These results suggest that the acquired sensitivity to EGF in these thyroid tumor cells may be responsible for the loss of differentiation in the transition toward a TSH-independent, invasive, and chemoresistant phenotype.
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