Abstract
Background
Anaplastic thyroid cancer is an endocrine malignancy. Its rare and rapidly lethal disease course has made it challenging to study. Little is known regarding the expression by anaplastic tumors of molecular targets for new human anticancer agents that have been studied in the preclinical or clinical setting. The objective of this work was to evaluate the expression profile of anaplastic thyroid tumors for molecular targets for treatment.
Methods
Of the 94 cases of anaplastic thyroid cancers diagnosed and treated in British Columbia, Canada over a 20-year period (1984–2004), 32 cases (34%) had adequate archival tissue available for evaluation. A tissue microarray was constructed from these anaplastic thyroid tumors and immunohistochemistry was utilized to evaluate expression of 31 molecular markers. The markers evaluated were: epidermal growth factor receptor (EGFR), HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, β-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, p53, MDM2, p21, Bcl-2, cyclin D1, cyclin E, p27, calcitonin, MIB-1, TTF-1, and thyroglobulin.
Results
A single tumor with strong calcitonin expression was identified as a poorly differentiated medullary carcinoma and excluded from the study cohort. The mean age of the anaplastic cohort was 66 years; 16 patients (51%) were females, and the median patient survival was 23 weeks. A wide range in molecular marker expression was observed by the anaplastic thyroid cancer tumors (0–100%). The therapeutic targets most frequently and most strongly overexpressed by the anaplastic tumors were: β-catenin (41%), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%).
Conclusions
Anaplastic thyroid tumors exhibit considerable derangement of their cell cycle and multiple signal transduction pathways that leads to uncontrolled cellular proliferation and the development of genomic instability. This report is the first to comprehensively evaluate a panel of molecular targets for therapy of anaplastic thyroid cancer and supports the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors, which may offer new hope for individuals diagnosed with this fatal thyroid malignancy.
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References
O’Neill JP, O’Neill B, Condron C, et al. Anaplastic (undifferentiated) thyroid cancer: improved insight and therapeutic strategy into a highly aggressive disease. J Laryngol Otol 2005; 119:585–591
Are C, Shaha AR. Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol 2006; Epub ahead of print
Ain KB. Anaplastic thyroid carcinoma: a therapeutic challenge. Semin in Surg Oncol 1999; 16:64–69
Tennvall J, Lundell G, Wahlberg P, et al. Anaplastic thyroid carcinoma: three protocols combining doxorubicin, hyperfractionated radiotherapy and surgery. Br J Cancer 2002; 86:1848–1853
Crevoisier RD, Baudin E, Bachelot A, et al. Combined treatment of anaplastic thyroid carcinoma with surgery, chemotherapy and hyperfractionated accelerated external radiotherapy. Int J Radiat Oncol Biol Phys 2004; 60:1137–1143
Artega CL, Moulder S, Yakes F. HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Semin Oncol 2002; 29:4–10
Chung KY, Saltz LB. Antibody-based therapies for colorectal cancer. Oncologist 2005; 10:701–709
Comis RL. The current situation: erlotinib (Tarceva©) and gefitinib (Iressa©) in non-small cell lung cancer. Oncologist 2005; 10:467–470
Sanborn RE, Blanke CD. Gastrointestinal stromal tumors and the evolution of targeted therapy. Clin Adv Hematol Oncol 2005; 3:647–657
Siegel-Lakhai WS, Beijnen JH, Schellens JHM. Current knowledge and future directions of the selective epidermal growth factor receptor inhibitors erlotinib (Tarceva©) and gefitinib (Iressa©). Oncologist 2005; 10:579–589
Parker RL, Huntsman DG, Lesack DW, et al. Assessment of interlaboratory variation in the immunohistochemical determination of estrogen receptor status using a breast cancer tissue microarray. Am J Clin Pathol 2002; 117:723–728
Liu CL, Prapong W, Natkunam Y, et al. Software tools for high-throughput analysis and archiving of immunohistochemistry staining data obtained with tissue microarrays. Am J Pathol 2002; 161:1557–1565
Wiseman S, Loree TR, Rigual NR, et al. Anaplastic transformation of thyroid cancer: review of clinical, pathologic, and molecular evidence provides new insights into disease biology and future therapy. Head Neck 2003; 25:662–670
McIver B, Hay ID, Giuffrida DF, et al. Anaplastic thyroid carcinoma: a 50-year experience at a single institution. Surgery 2001; 130:1028–1034
Venkatesh YS, Ordonez NG, Schultz PN, et al. Anaplastic carcinoma of the thyroid. A clinicopathologic study of 121 cases. Cancer 1990; 66:321–330
Heldin NE, Westermark B. The molecular biology of the human anaplastic thyroid carcinoma cell. Thyroidology 1991; 3:127–131
Hoffmann S, Wunderlich A, Celik I, et al. Paneling human thyroid cancer cell lines for candidate proteins for targeted anti-angiogenic therapy. J Cell Biochem 2006; Epub ahead of print
Lewin, Genes VII. (2000) New York: Oxford University Press, p 875
Onda M, Emi M, Yoshida A, et al. Comprehensive gene expression profiling of anaplastic thyroid cancers with cDNA microarrary of 25 344 genes. Endo-Rel Cancer 2004; 11:843–854
Ralfkiaer N, Gatter KC, Alcock C, et al. The value of immunocytochemical methods in the differential diagnosis of anaplastic thyroid tumours. Br J Cancer 1985; 52:167–170
Holting T, Moller P, Tschahargane C, et al. Immunohistochemical reclassification of anaplastic carcinoma reveals small and giant cell lymphoma. World J Surg 1990; 14:291–294
Ensinger C, Spizzo G, Moser P, et al. Epidermal growth factor receptor as a novel therapeutic target in anaplastic thyroid carcinomas. Ann NY Acad Sci 2004; 1030:69–77
Rosai J. Immunohistochemical markers of thyroid tumors: significance and diagnostic applications. Tumori 2003; 89:517–519
Ordonez NG, El-Naggar AK, Hickey RC, et al. Anaplastic thyroid carcinoma. Immunocytochemical study of 32 cases. Am J Clin Pathol 1991; 96:15–24
Lam KY, Lo CY, Chan KW, et al. Insular and anaplastic carcinoma of the thyroid: a 45-year comparative study at a single institution and a review of the significance of p53 and p21. Ann Surg 2000; 231:329–338
Erickson LA, Jin L, Wollan PC, et al. Expression of p27kip1 and Ki-67 in benign and malignant thyroid tumors. Mod Pathol 1998; 11:169–174
Urrutiocechea A, Smith IE, Dowsett M. Proliferation marker Ki-67 in early breast cancer. J Clin Oncol 2005; 23:7212–7220
Ross JS, Gray GS. Targeted therapy for cancer: the HER-2/neu and Herceptin story. Clin Leadersh Manag Rev 2003; 17:333–340
Ensinger C, Prommegger R, Kendler D, et al. Her2/neu expression in poorly differentiated and anaplastic thyroid carcinomas. Anticancer Res 2003; 23:2349–2353
Hiasa Y, Nishioka H, Kitahori Y, et al. Immunohistochemical analysis of estrogen receptors in 313 paraffin section cases of human thyroid tissue. Oncology 1993; 50:132–136
Younes MN, Kim S, Yigitbasi OG, et al. Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. Mol Cancer Ther 2005; 4:1146–1156
Vella V, Sciacca L, et al. The IGF system in thyroid cancer: new concepts. Mol Pathol 2001; 54:121–124
Brabant G, Hoang-Vu C, Cetin Y, et al. E-cadherin: a differentiation marker in thyroid malignancies. Cancer Res 1993; 53:4987–4993
Tallini G, Santoro M, Helie M, et al. RET/PTC oncogene activation defines a subset of papillary thyroid carcinomas lacking evidence of progression to poorly differentiated or undifferentiated tumor phenotypes. Clin Cancer Res 1998; 4:287–294
Sorrentino R, Libertini S, Pallante PL, et al. Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 2005; 90:928–935
Podtcheko A, Ohtsuru A, Tsuda S, et al. The selective tyrosine kinase inhibitor, ST1571, inhibits growth of anaplastic thyroid cancer cells. J Clin Endocrinol Metab 2003; 88:1889–1896
Dziba JM, Ain KB. Imatinib mesylate (Gleevec;STI571) monotherapy is ineffective in suppressing human anaplastic thyroid carcinoma cell growth in vitro. J Clin Endocrinol Metab 2004; 89:2127–2135
Schwartz GK, Shah MA. Targeting the cell cycle: a new approach to cancer therapy. J Clin Oncol 2005; 23:9408–9421
Yoshida A, Fukazawa M, Ushio H, et al. Study of cell kinetics in anaplastic thyroid carcinoma transplanted to nude mice. J Surg Oncol 1989; 42:1–4
Wang S, Lloyd RV, Hutzler MJ, et al. The role of cell cycle regulatory protein, cyclin D1, in the progression of thyroid cancer. Pathology 2000; 13:882–887
Bargonetti J, Manfredi JJ. Multiple roles of the tumor suppressor p53. Curr Opin Oncol 2002; 14:86–91
Moretti F, Farsetti A, Soddu S, et al. p53 re-expression inhibits proliferation and restores differentiation of human thyroid anaplastic carcinoma cells. Oncogene 1997; 14:729–740
Blagosklonny MV, Giannakakou P, Wojtowicz M, et al. Effects of p53-expressing adenovirus on the chemosensitivity and differentiation of anaplastic thyroid cancer cells. J Clin Endocrinol Metab 1998; 83:2516–2522
Fagin JA, Tang SH, Zeki K, Di Lauro R, Fusco A, Gonsky R. Reexpression of thyroid peroxidase in a derivative of an undifferentiated thyroid carcinoma cell line by introduction of wild-type p53. Cancer Res 1996; 56:765–771
Buolamwini JK, Addo J, Kamath S, et al. Small molecule antagonists of the MDM2 oncoprotein as anticancer agents. Curr Cancer Drug Targets 2005; 5:57–68
Kim R, Tanabe K, Uchida Y, et al. Effect of Bcl-2 antisense oligonucleotide on drug-sensitivity in association with apoptosis in undifferentiated thyroid carcinoma. Int J Mol Med 2003; 11:799–804
Dziba JM, Marcinek R, et al. Combretastatin A4 phosphate has primary antineoplastic activity against human anaplastic thyroid carcinoma cell lines and xenograft tumors. Thyroid 2002; 12:1063–1070
Straight AM, Oakley K, Moores R, et al. Aplidin reduces growth of anaplastic thyroid cancer xenografts and the expression of several angiogenic genes. Cancer Chemother Pharmacol 2006; 57:7–14
Schoenberger J, Grimm D, Kossmehl P, et al. Effects of PTK787/ZK222584, a tyrosine kinase inhibitor, on the growth of a poorly differentiated thyroid carcinoma: an animal study. Endocrinology 2004; 145:1031–1038
Kim S, Yazici YD, Barber S, et al. Growth inhibition of orthotopic anaplastic thyroid carcinoma xenografts in nude mice by PTK787/ZK222584 and CPT-11. Head Neck 2006; Epub ahead of print
Bauer AJ, Terrell R, Doniparthi NK, et al. Vascular endothelial growth factor monoclonal antibody inhibits growth of anaplastic thyroid cancer xenografts in nude mice. Thyroid 2002; 12:953–960
Cardones AR, Banez LL. VEGF inhibitors in cancer therapy. Curr Pharm Des 2006; 12:387–394
Kim SJ, Shiba E, Taguchi T, et al. uPA receptor expression in benign and malignant thyroid tumors. Anticancer Res 2002; 22:387–393
Rono B, Romer J, Liu S, et al. Antitumor efficacy of a urokinase activation-dependent anthrax toxin. Mol Cancer Ther 2006; 5:89–96
Wiseman S, Masoudi H, Niblock P, et al. Derangement of the E-cadherin complex is involved in transformation of differentiated to anaplastic thyroid carcinoma. Am J Surg 2006; in press
Green SK, Karlsson MC, Ravetch JV, et al. Disruption of cell–cell adhesion enhances antibody-dependent cellular cytotoxicity: implications for antibody-based therapeutics of cancer. Cancer Res 2002; 62:6891–6900
Harrington EA, Bebbington D, Moore J, et al. VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo. Nat Med 2004; 10:262–267
Matthews N, Visintin C, Hartzoulakis B, et al. Aurora A and B kinases as targets for cancer: will they be selective for tumors? Expert Rev Anticancer Ther 2006; 6:109–120
Zaczek A, Brandt B, Bielawski KP. The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol Histopathol 2005; 20:1005–1015
Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005; 23:2445–2459
Bergström JD, Westermark B, Heldin NE. Epidermal growth factor receptor signaling activates met in human anaplastic thyroid carcinoma cells. Exper Cell Res 2000; 259:293–299
Kim S, Prichard CN, Younes MN, et al. Cetuximab and irinotecan interact synergistically to inhibit the growth of orthotic anaplastic thyroid carcinoma xenografts in nude mice. Clin Cancer Res 2006; 12:600–607
Schiff BA, McMurphy AB, Jasser SA, et al. Epidermal growth factor receptor (EGFR) is overexpressed in anaplastic thyroid cancer, and the EGFR inhibitor gefitinib inhibits the growth of anaplastic thyroid cancer. Clin Can Res 2004; 10:8594–8602
Nobuhara Y, Onoda N, Yamashita Y, et al. Efficacy of epidermal growth factor receptor-targeted molecular therapy in anaplastic thyroid cancer cell lines. Br J Cancer 2005; 92:110–116
Broxterman HJ, Georgopapadakou NH. Anticancer therapeutics: “addictive” targets, multi-targeted drugs, new drug combinations. Drug Resistance Updates 2005; 8:183–197
Kim S, Schiff BA, Yigitbasi OG, et al. Targeted molecular therapy of anaplastic thyroid carcinoma with AEE788. Mol Cancer Ther 2005; 4:632–640
Kurebayashi J, Yamamoto Y, Tanaka K. Additive antitumor effects of gefitinib and imatinib on anaplastic thyroid cancer cells. Cancer Chemother Pharmacol 2006; Epub ahead of print
Saltz L. Epidermal growth factor receptor-negative colorectal cancer: is there truly such an entity? Clin Colorectal Cancer 2005; 5:98–100
Acknowledgments
Dr Wiseman and Dr Huntsman are Michael Smith Foundation for Health Research Scholars.
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Wiseman, S.M., Masoudi, H., Niblock, P. et al. Anaplastic Thyroid Carcinoma: Expression Profile of Targets for Therapy Offers New Insights for Disease Treatment. Ann Surg Oncol 14, 719–729 (2007). https://doi.org/10.1245/s10434-006-9178-6
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DOI: https://doi.org/10.1245/s10434-006-9178-6