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Development of medullary thyroid carcinoma in transgenic mice expressing the RET protooncogene altered by a multiple
F M Michiels1, S Chappuis, B Caillou
1Laboratoire de Génétique Oncologique, Centre National de la RechercheScientifique, Institut Gustave Roussy, Villejuif, France.
Abstract:
Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome that comprises three clinical subtypes: MEN type 2A (MEN-2A), MEN type 2B (MEN-2B), and familial medullary thyroid carcinoma (FMTC). Medullary thyroid carcinoma (MTC), a malignant tumor arising from calcitonin-secreting thyroid C cells, is the cardinal disease feature of this syndrome, and mortality in affected MEN-2 patients is mainly caused by this malignancy. Germ-line mutations of the RET protooncogene, which encodes a receptor tyrosine kinase, are responsible for these three neoplastic-prone disorders. MEN2 mutations convert the RET protooncogene in a dominantly acting oncogene as a consequence of the ligand-independent activation of the tyrosine kinase. The majority of MEN2A and FMTC mutations are located in the extracellular domain and cause the replacement of one of five juxtamembrane cysteines by a different amino acid. To examine whether expression of a MEN2A allele of RET results in transformation of C cells, we have used the transgenic approach. Expression of the RET gene altered by a MEN2A mutation was targeted in C cells by placing the transgene under the control of the calcitonin gene-related peptide/calcitonin promoter. Animals of three independent transgenic mouse lines, which expressed the transgene in the thyroid, displayed overt bilateral C cell hyperplasia as early as 3 weeks of age and subsequently developed multifocal and bilateral MTC. Moreover, these tumors were morphologically and biologically similar to human MTC which afflicts MEN2 individuals. These findings provide evidence that the MEN2A mutant form of RET is oncogenic in parafollicular C cells and suggest that these transgenic mice should prove a valuable animal model for hereditary MTC.
Insights
Multiple endocrine neoplasia type 2 (MEN 2) is a genetic cancer syndrome. This study shows a specific RET gene mutation causes medullary thyroid carcinoma (MTC) in mice, creating a valuable model for hereditary MTC research.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Multiple endocrine neoplasia type 2 (MEN 2) is an inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC).
- Germ-line mutations in the RET protooncogene are the underlying cause of MEN 2, leading to ligand-independent activation of its tyrosine kinase.
- MEN 2 mutations transform the RET protooncogene into a dominantly acting oncogene.
Purpose of the Study:
- To investigate if the MEN 2A RET protooncogene allele can induce C cell transformation.
- To establish a transgenic mouse model for studying hereditary medullary thyroid carcinoma.
Main Methods:
- Utilized a transgenic approach, targeting RET gene expression with a MEN 2A mutation in thyroid C cells.
- Employed the calcitonin gene-related peptide/calcitonin promoter to drive transgene expression specifically in C cells.
- Generated and analyzed three independent transgenic mouse lines.
Main Results:
- Transgenic mice exhibited early-onset bilateral C cell hyperplasia (starting at 3 weeks).
- Mice subsequently developed multifocal and bilateral medullary thyroid carcinoma.
- The induced MTC tumors were morphologically and biologically comparable to human MTC in MEN 2 patients.
Conclusions:
- The MEN 2A mutant RET protooncogene is oncogenic in parafollicular C cells.
- These transgenic mice represent a valuable animal model for hereditary MTC research.
- The findings support the role of RET mutations in the pathogenesis of MEN 2-associated MTC.