Functional insulin receptors are overexpressed in thyroid tumors: Is this an early event in thyroid tumorigenesis?

BACKGROUND. Insulin receptor (IR), a member of the receptor tyrosine kinase family, is expressed in normal thyroid cells and affects thyroid cell proliferation and differentiation. METHODS. The authors measured IR content in benign and malignant thyroid tumors by three independent methods: a specific radioimmunoassay, 125I-insulin binding studies, and immunohistochemistry. The results obtained were compared with the IR content in paired, adjacent, normal thyroid tissue. To assess IR function in thyroid carcinoma cells, glucose uptake responsiveness to insulin was also studied in a human transformed thyroid cell line (B-CPAP) and in follicular carcinoma cells in primary culture. RESULTS. In 9 toxic adenomas, the average IR content was similar to that observed in the 9 paired normal thyroid tissue specimens from the same patients (2.2 ± 0.3 vs. 2.1 ± 0.3). In 13 benign nonfunctioning, or 'cold,' adenomas, the average IR content was significantly higher (P < 0.001) than in paired normal tissue specimens (4.3 ± 0.5 vs. 1.8 ± 0.1). In 12 papillary and 10 follicular carcinomas, IR content was significantly higher (P < 0.001) than in the adjacent normal thyroid tissue (4.0 ± 0.4 vs. 1.6 ± 0.2 and 5.6 ± 1.0 vs. 1.8 ± 0.2, respectively). The finding of a higher IR content in benign 'cold' adenomas and in thyroid carcinomas was confirmed by both binding and immunostaining studies. CONCLUSIONS. The current studies indicate that 1) IR content is elevated in most follicular and papillary differentiated thyroid carcinomas, and 2) IR content is also elevated in most benign follicular adenomas ('cold' nodules) but not in highly differentiated, hyperfunctioning follicular adenomas ('hot' nodules), which very rarely become malignant. This observation suggests that increased IR expression is not restricted to the thyroid malignant phenotype but is already present in the premalignant 'cold' adenomas. It may contribute, therefore, to thyroid tumorigenesis and/or represent an early event that gives a selective growth advantage to transformed thyroid cells.