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Expression of RET and its ligand complexes, GDNF/GFRalpha-1 and NTN/GFRalpha-2, in medullary thyroid carcinomas
T Frisk1, F Farnebo, J Zedenius
1Department of Molecular Medicine, Endocrine Tumor Unit, Karolinska Hospital, Stockholm, Sweden. tony.frisk@cmm.ki.se
Objective:
Mutations in the RET proto-oncogene are found in about one third of sporadic medullary thyroid carcinomas (MTCs), mostly affecting codon 918. Glial cell line derived neurotropic factor (GDNF) and its membrane-bound GDNF family receptor alpha (GFRalpha-1), as well as neurturin (NTN) and its membrane-bound receptor GFRalpha-2 form a complex with the RET product, a receptor tyrosine kinase, resulting in downstream signaling to the nucleus.
Design:
To elucidate the role of these RET ligands in MTC tumorigenesis, their expression was determined in 15 MTC samples, one papillary thyroid carcinoma (PTC) and three normal thyroid tissue specimens.
Methods:
The mRNA expression of RET, GDNF, GFRalpha-1, NTN and GFRalpha-2 was investigated by mRNA in situ hybridization, and confirmed by reverse transcription-PCR analysis.
Results:
None of the five genes was expressed in the normal thyroids or in the PTC. All MTCs showed expression of RET, 13 expressed GDNF, 12 expressed GFRalpha-1 and 9 expressed NTN and GFRalpha-2. In 7 of the tumors RET, GDNF and GFRalpha-1 were expressed at high levels, and in five of these seven tumors NTN and GFRalpha-2 genes were also expressed at high levels. The high level of expression was preferentially seen in tumor cells adjacent to stroma and connective tissue. All MTCs without expression of the RET ligands harbored the RET codon 918 mutation.
Conclusions:
The results suggest that this signaling pathway is important for MTC development, and that it may be activated by expression of the RET ligand complexes by the tumor cells themselves.
Insights
RET ligand signaling is crucial for medullary thyroid carcinoma (MTC) development. Tumor cells expressing RET ligands and their receptors may activate this pathway, driving MTC tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Mutations in the RET proto-oncogene are implicated in approximately one-third of sporadic medullary thyroid carcinomas (MTCs).
- The RET receptor tyrosine kinase interacts with glial cell line-derived neurotrophic factor (GDNF) and neurturin (NTN) ligand-receptor complexes, initiating downstream signaling.
- These interactions are critical for cellular development and function, including in thyroid cancer.
Purpose of the Study:
- To investigate the expression patterns of RET ligands (GDNF, NTN) and their receptors (GFRalpha-1, GFRalpha-2) in MTC.
- To determine the role of this signaling pathway in MTC tumorigenesis.
- To correlate ligand expression with RET proto-oncogene mutations.
Main Methods:
- Analysis of mRNA expression of RET, GDNF, GFRalpha-1, NTN, and GFRalpha-2 in 15 MTC samples, one papillary thyroid carcinoma (PTC), and three normal thyroid tissues.
- Utilized mRNA in situ hybridization and reverse transcription-polymerase chain reaction (RT-PCR) for gene expression analysis.
Main Results:
- None of the studied genes were expressed in normal thyroid or PTC tissues.
- All MTC samples expressed RET, with high expression of RET, GDNF, and GFRalpha-1 observed in 7 tumors.
- MTCs lacking RET ligand expression frequently harbored the RET codon 918 mutation, suggesting alternative activation mechanisms.
Conclusions:
- The RET ligand-receptor signaling pathway appears to play a significant role in MTC development.
- Tumor cells may autonomously activate this pathway through the expression of RET ligand complexes.
- Targeting this pathway could offer novel therapeutic strategies for MTC.