Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas.

BACKGROUND/AIMS: Somatostatin analogues inhibit cell proliferation by stimulation of distinct somatostatin receptor (SSTR) subtypes. In recent years, these compounds have been introduced into the therapy of advanced hepatocellular carcinoma (HCC). The efficacy of this treatment is under debate due to the controversial results of clinical trials. Despite the widespread clinical use of somatostatin analogues in HCC, little is known about the expression of each of the five SSTRs in these tumors. METHODS: We analyzed the expression of SSTR subtypes in 56 HCCs by immunohistochemistry using subtype-specific antibodies. Six of the samples were also investigated by RT-PCR using subtype-specific oligonucleotide primers. RESULTS: HCCs display differential, individual expression patterns as well as variable expression levels for SSTRs. The overall expression rate of SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5 is 46, 41, 64, 0, and 75%, respectively. No significant correlation was observed between SSTR expression and tumor stage, differentiation, histological tumor type, or underlying liver disease. CONCLUSIONS: Individual patterns and levels of SSTR expression might determine the response to treatment with somatostatin analogues in HCC. Selective treatment of these tumors based on the analysis of SSTR subtype expression might lead to an increase in response rates.

The cholecystokinin2-receptor mediates calcitonin secretion, gene expression, and proliferation in the human medullary thyroid carcinoma cell line, TT.

Gastrin-induced release of calcitonin from medullary thyroid carcinomas (MTC) is based on the expression of the cholecystokinin(2)-receptor (CCK(2)R) in these tumors. Recently, we have shown that the CCK(2)R is expressed not only in MTC but also in C-cells within the normal thyroid gland. The functions of the CCK(2)R in MTC and C-cells are largely unknown. We therefore explored the effects of gastrin-induced CCK(2)R stimulation in the highly differentiated MTC cell line, TT. CCK(2)R expression in TT-cells is detectable by RT-PCR as well as immunocytochemistry. Stimulation of the CCK(2)R by gastrin induces immediate release of calcitonin from TT-cells. Moreover, quantitative (LightCycler) RT-PCR demonstrates that gastrin stimulates transcription of the calcitonin and chromogranin A genes in TT-cells. TT-cell proliferation, assessed by counting of viable cells and (3)H-thymidine uptake, is markedly increased by gastrin. This effect is inhibited by the CCK(2)R-specific antagonist L-365,260. Our findings suggest physiological functions for the CCK(2)R in calcitonin-secretion and gene expression as well as a pathophysiological role in MTC proliferation. CCK(2)R antagonists might have therapeutic potential in these tumors.