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.

Matteo Landriscina, Annamaria Piscazzi, Annarita Fabiano, Francesca Maddalena, Eleonora Costantino, Anna Farese, Pantaleo Bufo, Mauro Cignarelli

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)629-637
Number of pages9
JournalThyroid
Volume19
Issue number6
Publication statusPublished - Jun 2009

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Thyrotropin
Thyroid Neoplasms
Epidermal Growth Factor Receptor
Intercellular Signaling Peptides and Proteins
Phenotype
Thyroid Gland
Neoplasms
Cell Proliferation
Follicular Adenocarcinoma
Taxoids
Actin Cytoskeleton
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
Cell Movement
Actins
Cell Differentiation
Up-Regulation
Down-Regulation
Epithelial Cells
Cell Line

ASJC Scopus subject areas

  • Medicine(all)

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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. / Landriscina, Matteo; Piscazzi, Annamaria; Fabiano, Annarita; Maddalena, Francesca; Costantino, Eleonora; Farese, Anna; Bufo, Pantaleo; Cignarelli, Mauro.

In: Thyroid, Vol. 19, No. 6, 06.2009, p. 629-637.

Research output: Contribution to journalArticle

Landriscina, M, Piscazzi, A, Fabiano, A, Maddalena, F, Costantino, E, Farese, A, Bufo, P & Cignarelli, M 2009, '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.', Thyroid, vol. 19, no. 6, pp. 629-637.
Landriscina, Matteo ; Piscazzi, Annamaria ; Fabiano, Annarita ; Maddalena, Francesca ; Costantino, Eleonora ; Farese, Anna ; Bufo, Pantaleo ; Cignarelli, Mauro. / 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. In: Thyroid. 2009 ; Vol. 19, No. 6. pp. 629-637.
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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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AU - Maddalena, Francesca

AU - Costantino, Eleonora

AU - Farese, Anna

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AU - Cignarelli, Mauro

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AB - 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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