This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vella, V. Articles by Belfiore, A. Search for Related Content PubMed PubMed Citation Articles by Vella, V. Articles by Belfiore, A.

A Novel Autocrine Loop Involving IGF-II and the Insulin Receptor Isoform-A Stimulates Growth of Thyroid Cancer

Istituto di Medicina Interna e di Malattie Endocrine e del Metabolismo, Cattedra di Endocrinologia, University of Catania, Ospedale Garibaldi (V.V., G.P., L.S., R.M., R.V., V.P.), 95123 Catania, Italy; and Dipartimento di Medicina Sperimentale e Clinica, Cattedra di Endocrinologia, University of Catanzaro, Policlinico Mater Domini (A.B.), 88100 Catanzaro, Italy

Address all correspondence and requests for reprints to: Prof. Riccardo Vigneri, Cattedra di Endocrinologia, Ospedale Garibaldi, 95123 Catania, Italy. E-mail: vigneri{at}mbox.unict.it

The insulin receptor (IR) occurs in two isoforms (IR-A and IR-B) resulting from alternative splicing of exon 11 of the gene. The IR-A isoform is predominantly expressed in fetal tissues and malignant cells and binds IGF-II with high affinity. We previously observed that IRs are overexpressed in thyroid cancer cells; now we evaluated whether these cells preferentially express IR-A and produce IGF-II, which would activate a growth-promoting autocrine loop. The IR content ranged 6.0–52.6 ng/100 µg cell membrane protein in thyroid cancer primary cultures (n = 8) and permanent cell lines (n = 6) vs. 1.2–1.7 in normal thyroid cells (n = 11 primary cultures; P < 0.0001). IR-A isoform relative abundance ranged from 36–79% in cancer cells (with the highest values in undifferentiated cancers) vs. 27–39% in normal cells. Similar results were obtained in normal vs. cancer thyroid tissue specimens. IGF-II caused IR autophosphorylation with an ED₅₀ of 1.5–40.0 nM in cancer cells vs. more than 100 nM in normal cells; IGF-II affinity correlated with the relative abundance of IR-A (r = 0.628; P < 0.0001). IGF-II was expressed in all cancer cells, highly expressed in anaplastic cells, and less expressed in normal cells.

In conclusion, malignant thyrocytes, especially when poorly differentiated, produce IGF-II and overexpress IR, predominantly as IGF-II-sensitive isoform A. A growth-promoting autocrine loop is activated, therefore, and may affect thyroid cancer biology.

This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (to A.B. and R.V.) and MURST (Cofin99, to A.B.).

¹ Recipient of a fellowship from the Giuseppe Alazio Foundation for cancer research.

² Recipient of a Federazione Italiana per la Ricerca sul Cancro fellowship.

Abbreviations: HNMPA, Hydroxy-2-naphthalenylmethyl phosphoric acid triacetoxymethyl ester; IGF-BP, IGF-binding protein; IR, insulin receptor; IGF-I-R, IGF-I receptor; MPR, mannose-6-phosphate receptor; PMSF, phenylmethylsulfonylfluoride.

This article has been cited by other articles:

				K. H. Surinya, B. E. Forbes, F. Occhiodoro, G. W. Booker, G. L. Francis, K. Siddle, J. C. Wallace, and L. J. Cosgrove An Investigation of the Ligand Binding Properties and Negative Cooperativity of Soluble Insulin-like Growth Factor Receptors J. Biol. Chem., February 29, 2008; 283(9): 5355 - 5363. [Abstract] [Full Text] [PDF]

				Q.-s. Ji, M. J. Mulvihill, M. Rosenfeld-Franklin, A. Cooke, L. Feng, G. Mak, M. O'Connor, Y. Yao, C. Pirritt, E. Buck, et al. A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo Mol. Cancer Ther., August 1, 2007; 6(8): 2158 - 2167. [Abstract] [Full Text] [PDF]

				C. Blanquart, C. Gonzalez-Yanes, and T. Issad Monitoring the Activation State of Insulin/Insulin-Like Growth Factor-1 Hybrid Receptors Using Bioluminescence Resonance Energy Transfer Mol. Pharmacol., November 1, 2006; 70(5): 1802 - 1811. [Abstract] [Full Text] [PDF]

				A. Aiello, G. Pandini, F. Frasca, E. Conte, A. Murabito, A. Sacco, M. Genua, R. Vigneri, and A. Belfiore Peroxisomal Proliferator-Activated Receptor-{gamma} Agonists Induce Partial Reversion of Epithelial-Mesenchymal Transition in Anaplastic Thyroid Cancer Cells Endocrinology, September 1, 2006; 147(9): 4463 - 4475. [Abstract] [Full Text] [PDF]

				L. Lu, D. Katsaros, A. Wiley, I. A. Rigault de la Longrais, H. A. Risch, M. Puopolo, and H. Yu The Relationship of Insulin-Like Growth Factor-II, Insulin-Like Growth Factor Binding Protein-3, and Estrogen Receptor-{alpha} Expression to Disease Progression in Epithelial Ovarian Cancer Clin. Cancer Res., February 15, 2006; 12(4): 1208 - 1214. [Abstract] [Full Text] [PDF]

				A. Denley, G. V. Brierley, J. M. Carroll, A. Lindenberg, G. W. Booker, L. J. Cosgrove, J. C. Wallace, B. E. Forbes, and C. T. Roberts Jr. Differential Activation of Insulin Receptor Isoforms by Insulin-Like Growth Factors Is Determined by the C Domain Endocrinology, February 1, 2006; 147(2): 1029 - 1036. [Abstract] [Full Text] [PDF]

				P. Haluska, J. M. Carboni, D. A. Loegering, F. Y. Lee, M. Wittman, M. G. Saulnier, D. B. Frennesson, K. R. Kalli, C. A. Conover, R. M. Attar, et al. In vitro and In vivo Antitumor Effects of the Dual Insulin-Like Growth Factor-I/Insulin Receptor Inhibitor, BMS-554417 Cancer Res., January 1, 2006; 66(1): 362 - 371. [Abstract] [Full Text] [PDF]

				P Cabanas, T Garcia-Caballero, J Barreiro, L Castro-Feijoo, R Gallego, T Arevalo, R Canete, and M Pombo Papillary thyroid carcinoma after recombinant GH therapy for Turner syndrome Eur. J. Endocrinol., October 1, 2005; 153(4): 499 - 502. [Abstract] [Full Text] [PDF]

				D Fuhrer, M Eszlinger, S Karger, K Krause, C Engelhardt, D Hasenclever, H Dralle, and R Paschke Evaluation of insulin-like growth factor II, cyclooxygenase-2, ets-1 and thyroid-specific thyroglobulin mRNA expression in benign and malignant thyroid tumours Eur. J. Endocrinol., May 1, 2005; 152(5): 785 - 790. [Abstract] [Full Text] [PDF]

				J. P. Venables Aberrant and Alternative Splicing in Cancer Cancer Res., November 1, 2004; 64(21): 7647 - 7654. [Abstract] [Full Text] [PDF]

				A. Denley, E. R. Bonython, G. W. Booker, L. J. Cosgrove, B. E. Forbes, C. W. Ward, and J. C. Wallace Structural Determinants for High-Affinity Binding of Insulin-Like Growth Factor II to Insulin Receptor (IR)-A, the Exon 11 Minus Isoform of the IR Mol. Endocrinol., October 1, 2004; 18(10): 2502 - 2512. [Abstract] [Full Text] [PDF]

				V. Vella, R. Mineo, F. Frasca, E. Mazzon, G. Pandini, R. Vigneri, and A. Belfiore Interleukin-4 Stimulates Papillary Thyroid Cancer Cell Survival: Implications in Patients with Thyroid Cancer and Concomitant Graves' Disease J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2880 - 2889. [Abstract] [Full Text] [PDF]

				J. Wang, J. Grunler, and M. S. Lewitt Gender-Specific Pattern of Insulin-Like Growth Factor-Binding Protein-3 Protease Activity in Mouse Thyroid Endocrinology, March 1, 2004; 145(3): 1137 - 1143. [Abstract] [Full Text] [PDF]

				G. Pandini, E. Medico, E. Conte, L. Sciacca, R. Vigneri, and A. Belfiore Differential Gene Expression Induced by Insulin and Insulin-like Growth Factor-II through the Insulin Receptor Isoform A J. Biol. Chem., October 24, 2003; 278(43): 42178 - 42189. [Abstract] [Full Text] [PDF]

				L. Sciacca, M. Prisco, A. Wu, A. Belfiore, R. Vigneri, and R. Baserga Signaling Differences from the A and B Isoforms of the Insulin Receptor (IR) in 32D Cells in the Presence or Absence of IR Substrate-1 Endocrinology, June 1, 2003; 144(6): 2650 - 2658. [Abstract] [Full Text] [PDF]