title: A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis.
abstract: Hereditary medullary thyroid carcinoma (MTC) is caused by germline mutations in the RET proto-oncogene, resulting in constitutive activation of the RET tyrosine kinase. A substantial proportion of sporadic MTCs also have RET mutations, making the RET tyrosine kinase a potential therapeutic target in MTC. We have established a transplantable MTC in nude mice from a sporadic human MTC carrying a RET C634R mutation. Transplanted tumors had an exponential growth rate with an approximate doubling time of about 3 weeks, and expressed a neuroendocrine phenotype characteristic of MTC, e.g., expression of calcitonin, chromogranin A (CgA), synaptophysin, synaptic vesicle protein 2 (SV2), vesicular monoamine transporter-1 and -2, carcinoembryonic antigen, cytokeratin 8/18, epithelial cadherin, and neural cell adhesion molecule. Plasma calcitonin and CgA levels were elevated in tumor-bearing mice and correlated with tumor size. Cytogenetic analysis, including spectral karyotyping, confirmed the human origin of the xenografted tumors and demonstrated an abnormal, near triploid karyotype. Treatment of tumor-bearing nude mice with the tyrosine kinase inhibitor ZD6474, which specifically inhibits RET, epidermal growth factor receptor (EGFR), and vascular endothelium growth factor receptor (VEGFR) tyrosine kinases, resulted in a dose-dependent inhibition of tumor growth. Oral ZD6474 given once daily (250 mg/kg, 5 days/week) reduced tumor volume to 11% when compared with controls after 4 weeks. Our results show that this transplantable MTC, designated GOT2, represents a novel and useful model for studies of MTC and RET tyrosine kinase-dependent tumor growth.
authors.affiliation: Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. viktor.johanson@medfak.gu.se
authors.forename: Viktor
authors.initials: V
authors.lastname: Johanson
authors.forename: Håkan
authors.initials: H
authors.lastname: Ahlman
authors.forename: Peter
authors.initials: P
authors.lastname: Bernhardt
authors.forename: Svante
authors.initials: S
authors.lastname: Jansson
authors.forename: Lars
authors.initials: L
authors.lastname: Kölby
authors.forename: Fredrik
authors.initials: F
authors.lastname: Persson
authors.forename: Göran
authors.initials: G
authors.lastname: Stenman
authors.forename: Christina
authors.initials: C
authors.lastname: Swärd
authors.forename: Bo
authors.initials: B
authors.lastname: Wängberg
authors.forename: Mats
authors.initials: M
authors.lastname: Stridsberg
authors.forename: Ola
authors.initials: O
authors.lastname: Nilsson
mesh_terms: D000368:Aged; D000818:Animals; D002116:Calcitonin / Q000097:blood; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D053379:Chromogranin A / Q000097:blood; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D007621:Karyotyping; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D053379:Chromogranin A; C000715470:MAS1 protein, human; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D002116:Calcitonin; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; C452423:vandetanib