Human Somatostatin Receptor Subtypes in Acromegaly: Distinct Patterns of Messenger Ribonucleic Acid Expression and Hormone Suppression Identify Different Tumoral Phenotypes

Abstract

Recently, studies using somatostatin (SRIF) analogs preferential for either the SRIF receptor 2 (SSTR2) or the SSTR5 subtype demonstrated a variable suppression of GH and PRL release from GH-secreting human adenomas. These data suggested the concept of SSTR subtype specificity in such tumors. In the present study the quantitative expression of messenger ribonucleic acid (mRNA) for the 5 SSTR subtypes and the inhibitory effects of SRIF14; SRIF28; octreotide; the SSTR2-preferential analog, BIM-23197; and the SSTR5-preferential analog, BIM-23268, on GH and PRL secretion were analyzed in cells cultured from 15 acromegalic tumors. RT-PCR analysis revealed a consistent pattern of SSTR2 and SSTR5 mRNA expression. SSTR5 mRNA was expressed at a higher level (1052 +/- 405 pg/pg glyceraldehyde-3-phosphate dehydrogenase) than SSTR2 mRNA (100 +/- 30 pg/pg glyceraldehyde-3-phosphate dehydrogenase). However, only SSTR2 mRNA expression correlated with the degree of GH inhibition induced by SRIF14, SRIF28, and BIM-23197. The SSTR5-preferential compound inhibited GH release in only 7 of 15 cases. In cells cultured from the 10 mixed adenomas that secreted both GH and PRL, RT-PCR analysis revealed a consistent coexpression of SSTR5, SSTR2, and SSTR1 mRNA. In all cases SRIF14, SRIF28, and the SSTR5-preferential analog, BIM-23268, significantly suppressed PRL secretion, with a mean maximal inhibition of 48 +/- 4%. In contrast, the SSTR2-preferential analogs, BIM-23197 and octreotide, were effective in suppressing PRL in only 6 of 10 cases. In cells cultured from adenomas taken from patients partially responsive to the SRIF analog, octreotide, partial additivity in suppressing both GH and PRL secretion was observed when the SSTR2- and SSTR5-preferring analogs, BIM-23197 and BIM-23268, were tested in combination. Our data show a highly variable ratio of the SSTR2 and SSTR5 transcripts, according to tumors. The SSTR2-preferring compound consistently inhibits GH release, whereas the SSTR5-preferring compound is the main inhibitor of PRL secretion. When both drugs are combined, the partial additivity observed in mixed GH- plus PRL-secreting adenomas may be of interest in the therapeutic approach of such tumors.

Antitumor effects of somatostatin

“…In addition, somatostatin analog therapy is associated with tumor shrinkage in 37-82 % of patients receiving somatostatin analog as primary medical therapy (Bevan 2005;Melmed et al, 2005;Cozzi et al, 2003;Maiza et al, 2007). The efficacy of analogs on tumor growth is attributed to sst 2 and sst 5 whose expression predominates in growth hormone-secreting adenomas (Jaquet et al, 2000). Recent data argue in favour of a dissociation between antiproliferative and antisecretory effects of somatostatin analogs, their antitumor effect occuring independently of their antihormonal effect (Cozzi et al, 2006;Maiza et al, 2007).…”

Preclinical and clinical experiences with the role of somatostatin receptors in the treatment of pituitary adenomas

“…sst 2 and sst 5 receptors are the predominantly expressed sst, both at the mRNA (Table 1; (16)(17)(18)(19)) and the protein level (20). Several studies reported a variable sst 2 mRNA expression and a relatively high expression of sst 5 (16,18,21).…”

Somatostatin receptors subtypes 2 and 5, dopamine receptor type 2 expression and gsp status as predictors of octreotide LAR® responsiveness in acromegaly

“…Despite the fact that most studies suggest that gsp-positive adenomas respond better to octreotide LAR ® compared to gsp-negative tumors, a recent study failed to fi nd differences in octreotide LAR ® sensitivity according to gsp status (18). In addition, expression profi les of the mRNA somatostatin receptor subtypes (SSTR) in tumor fragments may serve as a predictive tool of biochemical and tumor volume response to SA therapy (24,(27)(28)(29)(30)(31)(32).…”