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Transforming growth factor beta receptors and p27kip in thyroid carcinoma
C A Muro-Cacho1, T Muñoz-Antonia, S Livingston
1Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute and University of South Florida College of Medicine, Tampa 33612, USA. murocacho@moffitt.usf.edu
Objective:
To investigate the role of cell cycle regulators in the pathogenesis of papillary carcinoma of the thyroid.
Design:
Resistance to transforming growth factor beta-mediated inhibition is a well-known pathogenic mechanism in epithelial neoplasias. In a retrospective study, the expression of transforming growth factor beta receptors types I and II, cyclin D1, and the cyclin-dependent inhibitor p27kip, was analyzed by immunohistochemistry. Results were interpreted in the context of clinicopathological data. Patient follow-up ranged from 1 to 18 years, with a mean of 4 years.
Materials:
Twenty conventional primary papillary carcinomas and their metastases were selected according to current pathologic criteria. Nonconventional papillary carcinomas (eg, tall-cell, columnar) were excluded from the analysis.
Results:
Cyclin D1 was expressed more intensely in the tumor than in adjacent nonneoplastic parenchyma. Within a given tumor, however, there was significant heterogeneity in expression intensity and percentage of positive cells, particularly in metastases. Type I receptors were strongly expressed in 90% of tumors, while 80% of the tumors revealed low to no expression of type II receptors. In 10% of tumors, type I receptors were absent and type II receptors expressed. Simultaneous absence of both receptors was not observed. While p27kip was strongly expressed in nonneoplastic thyroid, it was not detected in any of the primary tumors or their metastases.
Conclusions:
The results strongly suggest that functional abnormalities in type II receptors result in increased levels of cyclin D1 and down-regulation of p27kip. This would maintain cells in a proliferative state and would promote tumor progression.
Insights
Dysregulation of cell cycle regulators, specifically transforming growth factor beta receptor type II, contributes to papillary thyroid carcinoma progression by increasing cyclin D1 and decreasing p27kip. This promotes uncontrolled cell proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Papillary thyroid carcinoma pathogenesis involves resistance to transforming growth factor beta (TGF-β)-mediated growth inhibition.
- Cell cycle regulators play a crucial role in epithelial neoplasias.
Purpose of the Study:
- To investigate the role of cell cycle regulators in papillary thyroid carcinoma pathogenesis.
- To analyze the expression of TGF-β receptors (types I and II), cyclin D1, and p27kip in thyroid tumors.
Main Methods:
- Retrospective analysis of 20 conventional primary papillary carcinomas and their metastases using immunohistochemistry.
- Assessment of transforming growth factor beta receptor type I, transforming growth factor beta receptor type II, cyclin D1, and p27kip expression.
- Correlation of expression patterns with clinicopathological data.
Main Results:
- Cyclin D1 showed higher expression in tumors than normal tissue, with significant heterogeneity in metastases.
- Transforming growth factor beta receptor type I was highly expressed in most tumors (90%), while type II receptors showed low/no expression in 80%.
- p27kip was strongly expressed in non-neoplastic thyroid tissue but undetectable in primary tumors and metastases.
Conclusions:
- Functional abnormalities in transforming growth factor beta receptor type II appear to drive increased cyclin D1 levels and reduced p27kip.
- These molecular alterations likely contribute to maintaining a proliferative state and promoting tumor progression in papillary thyroid carcinoma.