Fibroblast growth factor receptors as molecular targets in thyroid carcinoma.
Several molecular abnormalities of potential therapeutic target value have been described in thyroid neoplastic transition. We report the expression of the fibroblast growth factor receptor family (FGFR-1-4) in normal thyroid tissues, human thyroid cancers of various types and behaviors, and cell lines representative of the spectrum of differentiation of tumors derived from follicular epithelial cells. FGFR-2 was the only receptor consistently detected in normal human thyroid tissue, and its expression diminished in all thyroid cancers and carcinoma cell lines, suggesting that it may have a protective role. FGFR-1 and FGFR-3 were expressed in most well-differentiated tumor types. FGFR-4, however, was expressed predominantly in aggressive tumor types and the most rapidly proliferative cell lines, indicating that it may promote the progression of these tumors. To specifically determine the function of FGFR-4 in thyroid carcinoma, gain- or loss-of-function studies were performed in cell lines representative of the spectrum of thyroid cancer behavior. Introduction of FGFR-4 resulted in enhanced cell proliferation, an effect that was more pronounced in cell lines derived from aggressive tumors than in those derived from more indolent neoplasms. Moreover, transduction of a dominant-negative FGFR attenuated cell proliferation in the aggressive poorly differentiated cell lines with no appreciable effect in well-differentiated cells. Pharmacologic FGFR-4 tyrosine kinase inhibition resulted in significant proliferation arrest in an aggressive cell line endogenously expressing the receptor. Furthermore, systemic administration of the FGFR tyrosine kinase inhibitor PD173074 resulted in significant inhibition of follicular thyroid carcinoma-derived cell growth in xenografted severe combined immunodeficient mice. These data indicate a role for FGFR-4 in human thyroid cancer cell progression and provide a rationale for FGFR manipulation as a potentially novel therapeutic approach.
St Bernard
Rosanne
R
Department of Pathology, University Health Network and University of Toronto, Toronto, Ontario, Canada.
Zheng
Lei
L
Liu
Wei
W
Winer
Daniel
D
Asa
Sylvia L
SL
Ezzat
Shereen
S
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002277:Carcinoma / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013961:Thyroid Gland / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism*; D013997:Time Factors
D004396:Coloring Agents; C115711:PD 173074; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D013778:Tetrazolium Salts; D013844:Thiazoles; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; C496371:FGFR4 protein, human; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; C496366:Fgfr3 protein, mouse; C496372:Fgfr4 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; C022616:thiazolyl blue