A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis
2007 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, Vol. 14, no 2, 433-444 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2007. Vol. 14, no 2, 433-444 p.
Aged, Animals, Calcitonin/blood, Carcinoma; Medullary/*drug therapy/enzymology/pathology, Cell Line, Tumor, Cell Transformation, Neoplastic/drug effects, Chromogranin A/blood, Disease Models, Animal, Humans, Karyotyping, Male, Mice, Mice, Nude, Mutation, Piperidines/pharmacology, Protein Kinase Inhibitors/pharmacology, Protein-Tyrosine Kinases/antagonists & inhibitors/genetics/metabolism, Proto-Oncogene Proteins c-ret/*antagonists & inhibitors/genetics/metabolism, Quinazolines/pharmacology, Receptor, Epidermal Growth Factor/antagonists & inhibitors, Thyroid Neoplasms/*drug therapy/enzymology/pathology, Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors, Xenograft Model Antitumor Assays
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-15955DOI: 10.1677/ERC-06-0033ISI: 000248720300021PubMedID: 17639056OAI: oai:DiVA.org:uu-15955DiVA: diva2:43726