Epidermal growth factor (EGF)- and transforming growth factor alpha-stimulated invasion and growth of follicular thyroid cancer cells can be blocked by antagonism to the EGF receptor and tyrosine kinase in vitro.
We have shown recently that epidermal growth factor (EGF) enhanced invasion and growth of differentiated thyroid cancer cells in vitro and in vivo. The present study analyzed the effects of transforming growth factor alpha (TGF-alpha) on invasion and growth of a follicular thyroid cancer cell line (FTC133) and whether blocking the EGF receptor by a monoclonal antibody (Mab528) or blocking the tyrosine kinase of the receptor by genistein abolished the EGF- and TFG-alpha-mediated effects. Growth and invasion (penetration of 8-microns pore polycarbonate membranes coated with Matrigel) were determined by the dimethylthiazol-diphenyltetrazolium bromide assay. Epidermal growth factor (10 ng/l) stimulated invasion of FTC133 by 42% and TGF-alpha (10 ng/l) stimulated invasion of FTC133 by 27% (p < 0.02). Both growth factors also enhanced growth by 62% (EGF) and 30% (TGF-alpha) (p < 0.003). Epidermal growth factor receptor antibodies (1 microgram/ml) abolished EGF-mediated stimulation of invasion and growth completely and that of TGF-alpha by 93%. At 100 ng/ml genistein reversed EGF and TGF-alpha stimulation, and at 1 microgram/ml it inhibited invasion (27%) and growth (40%) of unstimulated FTC133 (p < 0.02). We conclude that TGF-alpha stimulates invasion and growth of follicular thyroid cancer by binding to the EGF receptors, that EGF- and TGF-alpha-mediated effects can be blocked by antagonism to the EGF receptor and to tyrosine kinase, and that genistein not only neutralized EGF and TGF-alpha effects but also inhibited invasion and growth of unstimulated FTC133.(ABSTRACT TRUNCATED AT 250 WORDS)
Hölting
T
T
Surgical Service, Veterans Affairs Medical Center, San Francisco, CA.
Siperstein
A E
AE
Clark
O H
OH
Duh
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QY
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000276:immunology; D005260:Female; D019833:Genistein; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology*; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D007529:Isoflavones; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D019833:Genistein; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases