Evaluation of somatostatin biosynthesis, somatostatin receptors and tumor growth in murine medullary thyroid carcinoma

Abstract

Spontaneous medullary thyroid carcinomas (MTCs) of old rat thyroids were analyzed for the expression of somatostatin and somatostatin binding sites in tumoral C cells in relation to the stage of tumor development, the mitotic activity of tumoral tissue and calcitonin biosynthesis as a marker of C cell differentiation. High levels of both immunoreactive somatostatin and its mRNA were detected in a subpopulation of tumoral C cells, gathered in areas suggesting a clonal proliferation and located preferentially at the periphery of the tumor. These cells also displayed high levels of calcitonin and its mRNA. However, many calcitonin immunoreactive cells showed no sign of somatostatin synthesis. The proliferative activity of the somatostatin-containing areas was low and slow compared to the areas lacking somatostatin production. However, it increased during the course of tumor growth. Somatostatin binding sites, measured with in vitro receptor autoradiography using 125I-[Tyr3]-octreotide or 125I-[Leu8, dTrp22, Tyr25]SS-28, were not detected in any of the MTCs tested. In rat MTC cells, somatostatin was associated with differentiation and slow proliferation, two parameters inversely correlated with the progression of malignancy. As expected, owing to the highly regulated secretion of the differentiated endocrine cell type, its presence was correlated with low basal calcitonin levels. However, the absence of somatostatin binding sites on any type of MTC cells does not favor a direct autocrine regulation of this peptide in this murine model of human MTC.

Comparative immunohistochemical study of normal, hyperplastic and neoplastic C cells of the rat thyroid gland

“…Somatostatin was limited to a specific subset of C cells (Larsson 1985), which displayed a similar age-associated hyperplasia to non-somatostatin-positive C cells (Kakudo et al 1984). However, according to our results, and those obtained by Ouazzani et al (1994), in many C-cell tumours somatostatin is produced by the majority if not all neoplastic C cells. Consequently, there is a re-expression of this regulatory peptide with tumour development.…”

“…This pattern has also been described by O'Brian et al (1979) in nodular C-cell hyperplasia and some foci of neoplastic C cells in early MTC in rats. Ouazzani et al (1994) described a variable positivity for somatostatin among tumours in WAG/Rij rats, ranging from the entire tumoral mass to only some areas distributed at random, suggesting a clonal origin for somatostatin-positive cells at the beginning of tumour development. In human MTCs, though C cells expressing somatostatin were found in all tumours, they constituted only a few cells, singly or in small groups, scattered throughout the tumoral mass (Scopsi et al 1990;Neonakis et al 1994).…”

“…All the steps leading to the C-cell neoplasia have been described in the thyroid gland of different strains of old rats, including diffuse C-cell hyperplasia, focal C-cell hyperplasia and C-cell tumours Ouazzani et al 1994; Martín- Table 3 Immunohistochemical results obtained on C-cell carcinomas, specifying the maximal diameter of the tumours, the immunopositivity pattern for calcitonin and the percentage of somatostatin-positive C cells (CT calcitonin, CGRP calcitonin generelated peptide, CG chromogranin, SS somatostatin, ND non-determined; immunopositivities: -negative, + weak, ++ moderate, +++ strong, -/+++, +/++, +/+++, ++/+++ coexistence of C cells ranking from negative to strongly immunostained) Fig. 8A-C Serial sections of a C-cell carcinoma from rat no.…”

“…Only DeLellis et al (1979) and Lausson et al (1995) reported a correlation between the heterogeneity of calcitonin immunostaining and the advanced stage of the C-cell lesion. Ouazzani et al (1994) also analysed the expression of calcitonin and somatostatin peptides and mRNAs in relation to the stage of tumour development, concluding that somatostatin was associated with differentiation and slow proliferation.…”

Incretin Receptors in Non-Neoplastic and Neoplastic Thyroid C Cells in Rodents and Humans: Relevance for Incretin-Based Diabetes Therapy

“…Normal thyroids were obtained from Wistar and Sprague-Dawley rats, BALB/C and C57BL/6 mice. TT cells (ATCC-CRL-1803; LGC Standards, Teddington, UK), as well as nude mice xenografts from human TT cells, thyroids with C-cell hyperplasia or medullary thyroid carcinomas from old WAG/Rij rats (n = 11) or old MENx heterozygous mutant rats (n = 5) were taken from studies in which the tissues were used for other receptors determinations [14,16,17] (table 1). 36 human medullary thyroid carcinomas and 6 normal thyroids were surgical resection specimens characterized for peptide receptors in previous studies [18,19] that conformed to the ethical guidelines of the Institute of Pathology, University of Berne, and were reviewed by the Institutional Review Board.…”