Expression of Somatostatin Receptors 1-5 and Dopamine Receptor 2 in Lung Carcinoids: Implications for a Therapeutic Role

Abstract

Objective: The expression of somatostatin receptors (SSTRs) and dopamine receptor 2 (DR2) in neuroendocrine tumors is of clinical importance as somatostatin analogues and dopamine agonists can be used for their localization and/or treatment. The objective of this study is to examine the expression of the five SSTR subtypes and DR2 in lung carcinoids (LCs). Methods: We conducted a retrospective study of 119 LCs from 106 patients [typical carcinoids (TCs): n = 100, and atypical carcinoids (ACs): n = 19]. The expression of all five SSTR subtypes and DR2 was evaluated immunohistochemically and correlated to clinicopathological data. In a subgroup of cases, receptor expression was further analyzed using semiquantitative RT-PCR. Results: SSTR2A was the SSTR subtype most frequently expressed immunohistochemically (72%), followed by SSTR1 (63%), SSTR5 (40%), and SSTR3 (20%), whereas SSTR4 was negative. DR2 was expressed in 74% and co-expressed with SSTR1 in 56%, with SSTR2A in 59%, with SSTR3 in 19%, and with SSTR5 in 37% of the tumors. Receptor expression was not related to the histological subtype, tumor aggressiveness (disease extent/grading) or functionality; however, DR2 was expressed more frequently in ACs than TCs (95 vs. 70%, p = 0.017). In a subset of patients, RT-PCR findings highly suggested that the expression of SSTR2A, SSTR3, DR2, and to a lesser extent that of SSTR1 and SSTR5 is the outcome of increased gene transcription. Conclusions: The high and variable immunohistochemical expression of the majority of SSTRs along with their co-expression with DR2 in LCs provides a rationale for their possible treatment with agents that target these receptors.

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells

“…The siNET cell line KRJ-I demonstrated equal mRNA expression levels for SSTR1 and SSTR2 [3]. In most studies where the quantitative mRNA expression levels of SSTRs were studied, SSTR2 was more highly expressed than SSTR1 [40,41,42,43,44]. In general, there is a predominant expression of SSTR1 and SSTR2 mRNA in NETs, with highly variable mRNA expression levels [40,45].…”

Lung Carcinoids: Long-Term Surgical Results and the Lack of Prognostic Value of Somatostatin Receptors and Other Novel Immunohistochemical Markers

“…Tissue specimens from the included patients had previously been subjected to IHC staining using the following primary antibodies: polyclonal rabbit SSTR1–5 (SSTR1:SS-840; SSTR2A:SS-800; SSTR3:SS-850; SSTR4:SS-880; SSTR5:SS-890; Gramsch Laboratories, Schwabhausen, Germany) polyclonal rabbit DR2 (Novus Biologicals, Littleton, CO, USA), novel monoclonal rabbit anti-SSTR2A, UMB-1 (Epitomics Inc, Burlingame, CA, USA); polyclonal rabbit OR51E1 (LSBio, Seattle, WA, USA); polyclonal goat IGF-1 (C-20), sc-7144 (Santa Cruz Biotechnology, Inc.); polyclonal rabbit IGF-1 Receptor beta (C-20), sc-713 (Santa Cruz Biotechnology, Inc.); polyclonal goat CTGF (L-20), sc-14939 (Santa Cruz Biotechnology, Inc.) and mouse monoclonal HIF-1 alpha ESEE 122, NB100–131 (Novus Biologicals, Burlingame, CA, USA), as previously described in this patient cohort [11-13]. …”

“…Additionally, the localization of receptor expression was assessed semi-quantitatively based on the classification by Volante et al [19] as follows: Score 1 (S1): pure cytoplasmic immunoreactivity; score 2 (S2): a minority tumour cell population showed membranous immunoreactivity in < 50% of the cell circumference, and score 3 (S3): a majority tumour cell population revealed membranous immunoreactivity in over 50% of the circumference [11, 12, 19]. The intensity of IHC staining for the IGF-1, IGF -1R, CTGF and HIF-1 antibodies were rendered only quantitatively with a 50% cut-off [20].…”

“…The high and variable Immunohistochemical (IHC) expression of the majority of somatostatin receptors (SSTRs) along with their co-expression with dopamine receptor 2 (DR2), as well as the expression of olfactory receptor 51E1 (OR51E1) in SS-negative LCs, have been previously addressed, providing a rationale for potentially novel diagnostic markers that may be utilized as therapeutic targets [11, 12]. Additionally, the expression of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), connective tissue growth factor (CTGF) and hypoxia factor-1 (HIF-1) has recently been confirmed in these patients [13].…”

Cardiac Surgery for Carcinoid Heart Disease: A Weapon Not to Be Misused

“…The use of currently available long-acting somatostatin analogues (octreotide or lanreotide) aims at reducing the secretion of vasoactive peptides from the carcinoid tumor, leading to symptomatic relief and a decrease in urine levels of 5-HIAA, as well as stabilization of the tumor size in up to half of patients [12,13,14]. Aggressive treatment in order to decrease 5-HIAA below 300 mmol/24 h is advisable, as more recent studies have shown that following the prolonged use of somatostatin analogues the incidence of CHD substantially decreases from 50 to 20-25% [15].…”