Background: Medullary thyroid carcinoma(MTC)arises from malignant transformation of calcitonin-secreting neuroendocrine C-cells.Pentagastrin-induced stimulation of calcitonin-release is used as a diagnostic tool in the clinical management of patients with MTC.It has previously been shown that human MTCs express the COK~-rsceptor (CCK2R).However, it has remained unclear whether CCK2R expression is restricted to MTC or whether physiological expression of this receptor occurs in normal thyroid tissue.The aim of our study was to investigate expression of the CCK2R in samples of MTC, follicular thyroid carcinoma (FTC), normal thyroid tissue and C-cell hyperplasia.Methods: 19 MTC samples, TT-cells (a human MTC cell line), three samples of normal thyroid tissue, and one FTC were analyzed for CCK2R-expression by RT-PCR.Immunohistochemistry using CCK2R-and calcitonin-specific antibodies was performed in five MTCs and one sample of non-malignant C-cell hyperplasia.Results: CCK2R expression was found in 11 of the 19 MTC samples as well as in l-r-cells.Consistent with our previous findings, the incidence of the CCK2R was high in small tumors whereas in large metastasized tumors no receptor expression was detectable.The results of pentagastrinstimulation tests correlated positively with the expression of the CCK2R.In addition to MTCs, CCK2R-expression was detected by RT-PCR in FTC as well as in all samples of normal thyroid tissue.To further localize CCK2R-expression we performed immunhistochemistry in MTC and C-cell hyperplasia samples.Staining of consecutive tissue sections with specific antibodies against the CCK2R and calcitonin revealed that normal as well as malignant C-cells express the CCK~R.Discussion: Our study shows for the first time that the CCK2R is expressed in normal thyroid tissue, specifically in C-cells.This finding suggests that in C-cells the CCK2R has a physiologic function, possibly related to bone and calcium metabolism.The rise in calcitonin serum-levels after pentagastrin-stimulation in MTCs most likely reflects an increase in C-cell number rather than a mechanism specific for malignant C-cells.Given its well established effects on growth and differentiation of ELL-ceils, gastrin might exert similar functions on the closely related C-call and in early stages of MTC.Ongoing malignant growth and potential loss of differentiation in MTC appears to be associated with a loss of CCK2R expression in advanced tumor stages.