| 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. |
| Authors | Matteo Landriscina, Annamaria Piscazzi, Annarita Fabiano, Francesca Maddalena, Eleonora Costantino, Anna Farese, Pantaleo Bufo, Mauro Cignarelli
(Affiliation: Department of Medical Sciences, University of Foggia, Foggia, Italy. m.landriscina at unifg.it)
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| Journal | Thyroid : official journal of the American Thyroid Association
(Thyroid)
Vol. 19
Issue 6
Pg. 629-37
(Jun 2009)
ISSN: 1557-9077 [Electronic] United States |
| PMID | 19499990
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Antineoplastic Agents
- RNA, Neoplasm
- Tetrazolium Salts
- Thiazoles
- thiazolyl blue
- Thyrotropin
- Receptor, Epidermal Growth Factor
|
| Topics |
- Antineoplastic Agents
(therapeutic use)
- Blotting, Western
- Cell Differentiation
(drug effects)
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Cell Survival
(drug effects)
- Down-Regulation
(drug effects)
- Drug Resistance, Neoplasm
- Humans
- Microscopy, Confocal
- Neovascularization, Pathologic
(pathology)
- Phenotype
- RNA, Neoplasm
(biosynthesis, genetics)
- Receptor, Epidermal Growth Factor
(biosynthesis, drug effects, physiology)
- S Phase
(drug effects)
- Signal Transduction
(drug effects)
- Tetrazolium Salts
- Thiazoles
- Thyroid Neoplasms
(drug therapy, pathology)
- Thyrotropin
(physiology)
|
