Exp Clin Endocrinol Diabetes 2005; 113 - 90
DOI: 10.1055/s-2005-862949

The EGF/EGFR system as a possible target for anti tumor therapy in thyroid cancer

S Hoffmann 1, L Hofbauer 2, A Wunderlich 1, I Celik 3, A Zielke 1
  • 1Universitätsklinikum Marburg, Chirurgie, Marburg
  • 2Univeristätsklinik Marburg, Gastroenterologie SP Endokrinologie, Marburg
  • 3Universitätsklinikum Marburg, Theoretische Chirurgie, Marburg

Aim: The EGF/EGF-receptor (EGFR) system in thyroid neoplasia has long since been associated with de-differentiation, enhanced proliferation and angiogenesis. Angiogenesis is essential for tumor growth and VEGF is the main stimulator of angiogenesis in the thyroid. This study aimed to evaluate the EGF/EGFR system to regulate VEGF in thyroid cancer cell lines and to evaluate the potential of inhibitors to affect such regulation.

Methods: Immunohistochemical detection of EGFR was done in anaplastic (Hth74, C643), follicular (FTC133, HTC, HTCtshr), a Hürthle (XTC) and a papillary cancer cell line (TPC1). Basal and EGF/TGFa stimulated (1–100ng/ml) VEGF gene expression (steady state tRNA isolates hybridized w. full length VEGFcDNA) and secretion of VEGF protein (Quantikine EIA, R&D) were determined. The effect of a monopulse of EGF tyrosine inhibitor TB56 (0.001–10mcM) was evaluated in the anaplastic thyroid cancer cell line Hth74 with respect to proliferation (MTT cytotoxicity assay) and secretion of VEGF (EIA).

Main results: Positive immunostains for EGFR were obtained in all cell lines. Basal VEGF secretion different substantially among the cell lines. However, EGF and TGFa stimulated VEGF gene expression and secretion of protein by up to 20-fold (e.g. Hth74 1800 vs. 100 pg/ml, FTC 133 4500 vs. 1500 pg/ml at 100ng/ml EGF) and for more effectively than TSH. Induction of VEGF secretion was most pronounced in cell lines not expressing functioning TSHR. In anaplastic Hth74 cells, TB56 caused a dose dependent inhibition of proliferation with an average IC50 of 2.5mcM. At subcytotoxic concentrations of TB56, VEGF secretion was reduced by up to 70%.

Discussion: This is a first time description of EGF/EGFR to regulate VEGF gene expression and secretion of thyroid carcinoma cell lines. The EGF/EGFR system resembles a powerful pathway to induce VEGF and is particularly effective in the absence of TSHR. The antiproliferative and VEGF-suppressive effect of TB56 suggests, that targeting EGFR mediated pathways may have therapeutic potential in some undifferentiated thyroid cancer.