A transplantable human medullary thyroid carcinoma as a model for RET tyrosine kinase-driven tumorigenesis

• 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.

Nyckelord

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

MEDICINE

MEDICIN

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