Abstract
This study evaluated the role of EGF and the effects of EGF-targeting drugs (Cetuximab, AEE 788) on growth, apoptosis, and autocrine VEGF-secretion of thyroid cancer (TC) cells. Autocrine activation of the epidermal growth factor receptor (EGF-R) is commonly regarded to contribute to the malignant phenotype of TC cells and may therefore represent a rational therapeutic target. Out of a number of TC cell lines two anaplastic (Hth74, C643), one follicular (FTC133), and one papillary thyroid cancer cell line (TPC1) were analyzed in depth for VEGF-R-and EGF-R-expression, basal and EGF-stimulated (1–100 ng/ml) VEGF protein secretion and proliferation. Subsequently the antiprolifereative and antiangiogenic effect of cetuximab (Erbitux®), a monoclonal antibody that blocks the EGF-R and AEE 788, a novel dual-kinase inhibitor of EGF-R and VEGF-R were assessed, and the downstream EGF-R signal transduction was analyzed by means of detecting phosphorylated pEGF-R, pVEGF-R, pAkt, and p-MAPK. EGF stimulated VEGF-mRNA expression and protein secretion in all TC cell lines. The EGF-R antagonist Cetuximab consistently decreased VEGF secretion in all TC cell lines (min. 15%, n.s. in C643 cells and max. 90% in Hth74 cells, P < 0.05), but did not affect tumor cell proliferation in␣vitro. In contrast, the EGF-R- and VEGF-R-kinase inhibitor AEE 788 not only reduced VEGF secretion (min. 55%, P < 0.05 in C643 and max. 75%, P < 0.05, in FTC133), but also exhibited a dose-dependent inhibition of tumor cell proliferation (min. 75%, P < 0.05 in C643 and max. 95%, P < 0.05 in Hth74) and was a potent inductor of apoptosis in two of four TC cell lines. These effects were always accompanied by reduced levels of pEGF-R, pVEGF-R, pAkt, and pMAPK. Although inhibition of the EGF-receptor by Cetuximab potently disrupts autocrine secretion of VEGF, only the concurrent inhibition of the VEGF- and EGF receptor, e.g., by AEE 788 induces reduced proliferation and apoptosis in␣vitro. This suggests a particular rationale for the use of tyrosine kinase inhibitors with dual modes of action such as AEE 788 in thyroid cancer.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
N.R. Caron, O.H. Clark, Scand. J. Surg. 93, 261–267 (2004)
S. Diehl, C.B. Umbricht, A.P. Dackiw, M.A. Zeiger, Thyroid 15, 575–582 (2005)
K.B. Ain, Semin. Surg. Oncol. 16, 64–69 (1999)
B. McIver, I.D. Hay, D.F. Giuffrida, C.E. Dvorak, C.S. Grant, G.B. Thompson, J.A. van Heerden, J.R. Goellner, Surgery 130, 1028–1034 (2001)
J.L. Pasieka, Curr. Opin. Oncol. 15, 78–83 (2003)
J. Folkman, J. Natl. Cancer Inst. 82, 4–6 (1990)
D. Hanahan, J. Folkman, Cell 86, 353–364 (1996)
J.D. Ramsden, J. Endocrinol. 166, 475–480 (2000)
C.J. Hung, D.G. Ginzinger, R. Zarnegar, H. Kanauchi, M.G. Wong, E. Kebebew, O.H. Clark, Q.Y. Duh J. Clin. Endocrinol. Metab. 88, 3694–3699 (2003)
S. Hoffmann, L.C. Hofbauer, V. Scharrenbach, A. Wunderlich, I. Hassan, S. Lingelbach, A. Zielke J. Clin. Endocrinol. Metab. 89, 6139–6145 (2004)
J.D. Lin, T.C. Chao Cancer Biother. Radiopharm. 20, 648–661 (2005)
P. Siironen, J. Louhimo, S. Nordling, A. Ristimaki, H. Maenpaa, R. Haapiainen, C. Haglund, Tumour Biol. 26, 57–64 (2005)
E. Kebebew, M. Peng, E. Reiff, Q.Y. Duh, O.H. Clark, A. McMillan, Surgery 38, 1102–1109 (2005)
D.S. Kim, J.A. Franklyn, A.L. Stratford, K. Boelaert, J.C. Watkinson, M.C. Eggo, C.J. McCabe, J. Clin. Endocrinol. Metab. 91, 1119–1128 (2006)
E.Y. Soh, M.S. Eigelberger, K.J. Kim, M.G. Wong, D.M. Young, O.H. Clark, Q.Y. Duh, Surgery 128, 1059–1065 (2000)
A.J. Bauer, R. Terrell, N.K. Doniparthi, A. Patel, R.M. Tuttle, M. Saji, M.D. Ringel, G.L. Francis, Thyroid 12, 953–961 (2002)
A.J. Bauer, A. Patel, R. Terrell, K. Doniparthi, M. Saji, M. Ringel, R.M. Tuttle, G.L. Francis, Ann. Clin. Lab. Sci. 33, 192–199 (2003)
S. Hoffmann, A. Wunderlich, I. Celik, K. Maschuw, Y. Hassan, S. Lingelbach, A. Zielke, J. Cell. Biochem. 98, 954–965 (2006)
M.D. Ringel, N. Hayre, J. Saito, B. Saunier, F. Schuppert, H. Burch, V. Bernet, K.D. Burman, L.D. Kohn, M. Saji, Cancer Res. 61, 6105–6111 (2001)
V. Vasko, M. Saji, E. Hardy, M. Kruhlak, A. Larin, V. Savchenko, M. Miyakawa, O. Isozaki, H. Murakami, T. Tsushima, K.D. Burman, C. De Micco, M.D. Ringel, J. Med. Genet. 41, 161–170 (2004)
S.M. Freeman, K.A. Whartenby, Drug. News Perspect. 17, 237–242 (2004)
A.G. Fraumann, A.C. Moses, Metab. North Am. 19, 479–493 (1990)
Q.Y. Duh, E.T. Gum, P.L. Gerend, S.E. Raper, O.H. Clark, World J. Surg. 14, 410–418 (1990)
J.D. Bergstrohm, B. Westermark, N.E. Heldin, Exp. Cell Res. 259, 293–299 (2000)
L.A. Akslen, A.O. Myking, H. Salvesen, J.E. Varhaug, Br. J. Cancer 68, 808–812 (1993)
B.A. Schiff, A.B. McMurphy, S.A. Jasser, M.N. Younes, D. Doan, O.G. Yigitbasi, S. Kim, G. Zhou, M. Mandal, B.N. Bekele, F.C. Holsinger, S.I. Sherman, S.C. Yeung, A.K. El-Naggar, J.N. Myers, Cancer Res. 10, 8594–8602 (2004)
T. Hoelting, A.E. Siperstein, O.H. Clark, Q.Y. Duh, J. Clin. Endocrinol. Metab. 79, 401–408 (1994)
B. Gabler, T. Aicher, P. Heiss, R. Senekowitsch-Schmidtke, Anticancer Res. 17, 3157–3159 (1997)
E.S. Kim, F.R. Khuri, R.S. Herbst, Curr. Opin. Oncol. 13, 506–513 (2001)
G.P. Adams, L.M. Weiner, Nat. Biotechnol. 23, 1147–1157 (2005)
P. Traxler, P.R. Allegrini, R. Brandt, J. Brueggen, R. Cozens, D. Fabbro, K. Grosios, H.A. Lane, P. McSheehy, J. Mestan, T. Meyer, C. Tang, M. Wartmann, J. Wood, G. Caravatti, Cancer Res. 64, 4931–4941 (2004)
O.G. Yigitbasi, M.N. Younes, D. Doan, S.A. Jasser, B.A. Schiff, C.D. Bucana, B.N. Bekele, I.J. Fidler, J.N. Myers, Cancer Res. 64, 7977–7984 (2004)
M.N. Younes, O.G. Yigitbasi, Y.W. Park, S.J. Kim, S.A. Jasser, V.S. Hawthorne, Y.D. Yazici, M. Mandal, B.N. Bekele, C.D. Bucana, I.J. Fidler, J.N. Myers, Cancer Res. 65, 4716–4727 (2005)
A. Konturek, M. Barczynski, S. Cichon, A. Pituch-Noworolska, J. Jonkisz, W. Cichon, Langenbecks Arch. Surg. 390, 216–221 (2005)
A. Maity, N. Pore, J. Lee, D. Solomon, D.M. O’Rourke, Cancer Res. 60, 5879–5886 (2000)
J.M. Vieira, S.C. Santos, C. Espadinha, I. Correia, T. Vag, C. Casalou, B.M. Cavaco, A.L. Catarino, S. Dias, V. Leite, Eur. J. Endocrinol. 153, 701–709 (2005)
R.B. Luwor, Y. Lu, X. Li, J. Mendelsohn, Z. Fan, Oncogene 24, 4433–4441 (2005)
N. Pore, Z. Jiang, A. Gupta, G. Cerniglia, G.D. Kao, A. Maity, Cancer Res. 66, 3197–3204 (2006)
T. Karashima, P. Sweeney, J.W. Slaton, S.J. Kim, D. Kedar, J.I. Izawa, Z. Fan, C. Pettaway, D.J. Hicklin, T. Shuin, C.P. Dinney, Clin. Cancer Res. 8, 1253–1264 (2002)
Z.Q. Huang, D.J. Buchsbaum, K.P. Raisch, J.A. Bonner, K.I. Bland, S.M. Vickers, J. Surg. Res. 111, 274–283 (2003)
S. Kim, C.N. Prichard, M.N. Younes, Y.D. Yazici, S.A. Jasser, B.N. Bekele, J.N. Myers, Clin. Cancer Res. 12, 600–607 (2006)
J.P. Overholser, M.C. Prewett, A.T. Hooper, H.W. Waksal, D.J. Hicklin, Cancer 89, 74–82 (2000)
A.M. Mercurio, E.A. Lipscomb, R.E. Bachelder, J. Mammary Gland Biol. Neoplasia. 4, 283–290 (2005)
J. Kurebayashi, S. Okubo, Y. Yamamoto, M. Ikeda, K. Tanaka, T. Otsuki, H. Sonoo, Cancer Chemother. Pharmacol. 58, 460–470 (2006)
K.T. Chen, J.D. Lin, T.C. Chao, C. Hsueh, C.A. Chang, H.F. Weng, E.C. Chan, Thyroid 11, 41–46 (2001)
M.C. Specht, C.B. Barden, T.J. Fahey, Surgery 130, 936–940 (2001)
F. Kada, M. Saji, M.D. Ringel, Curr. Drug Targets. Immune. Endocr. Metabol. Disord. 4, 181–185 (2004)
K.L. Dunn, P.S. Espino, B. Drobic, S. He, J.R. Davie, Biochem. Cell. Biol. 83, 1–14 (2005)
C.S. Kim, V.V. Vasko, Y. Kato, M. Kruhlak, M. Saji, S.Y. Cheng, M.D. Ringel, Endocrinology 146, 4456–4463 (2005)
K. Yokoi, P.H. Thaker, S. Yazici, R.R. Rebhun, D.H. Nam, J. He, S.J. Kim, J.L. Abbruzzese, S.R. Hamilton, I.J. Fidler, Cancer Res. 65, 3716–3725 (2005)
S. Yazici, S.J. Kim, J.E. Busby, J. He, P. Thaker, K. Yokoi, D. Fan, I.J. Fidler, Prostate 65, 203–215 (2005)
P.H. Thaker, S. Yazici, M.B. Nilsson, K. Yokoi, R.Z. Tsan, J. He, S.J. Kim, I.J. Fidler, A.K. Sood, Clin. Cancer Res. 11, 4923–4933 (2005)
S. Kim, B.A. Schiff, O.G. Yigitbasi, D. Doan, S.A. Jasser, B.N. Bekele, M. Mandal, J.N. Myers, Mol. Cancer Ther. 4, 632–640 (2005)
Y. Ishizaka, F. Itoh, T. Tahira, I. Ikeda, T. Ogura, T. Sugimura, M. Nagao, Jpn. J. Cancer Res. 80, 1149–1152 (1989)
T. Hoelting, A. Zielke, A.E. Siperstein, O.H. Clark, Q.Y. Duh, Clin. Exp. Metastasis. 12, 315–323 (1994)
M. Derwahl, M. Kuemmel, P.E. Goretzki, H. Schatz, M. Broecker, Biochem. Biophys. Res. Commun. 191, 1131–1138 (1993)
A. Zielke, S. Tezelman, G.H. Jossart, M. Wong, A.E. Siperstein, Q.Y. Duh, O.H. Clark, Thyroid 8, 475–483 (1998)
N.E. Heldin, B. Westermark, Thyroidology 3, 127–131 (1991)
M. Middeke, S. Hoffmann, I. Hassan, A. Wunderlich, L.C. Hofbauer, A. Zielke, Exp. Clin. Endocrinol. Diabetes 110, 386–392 (2002)
A. Burchert, Y. Wang, D. Cai, N. von Bubnoff, P. Paschka, S. Muller-Brusselbach, O.G. Ottmann, J. Duyster, A. Hochhaus, A. Neubauer, Leukemia 19, 1774–1782 (2005)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hoffmann, S., Burchert, A., Wunderlich, A. et al. Differential effects of cetuximab and AEE 788 on epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) in thyroid cancer cell lines. Endocr 31, 105–113 (2007). https://doi.org/10.1007/s12020-007-0008-9
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-007-0008-9