GIPR expression in gastric and duodenal neuroendocrine tumors

Abstract

Background

Compounds targeting somatostatin-receptor-type-2 (SSTR2) are useful for small bowel neuroendocrine tumor (SBNET) and pancreatic neuroendocrine tumor (PNET) imaging and treatment. We recently characterized expression of 13 cell surface receptor genes in SBNETs and PNETs, identifying three drug targets (GIPR, OXTR, and OPRK1). This study set out to characterize expression of this gene panel in the less common neuroendocrine tumors of the stomach and duodenum (gastric and duodenal neuroendocrine tumors [GDNETs]).

Methods

Primary tumors and adjacent normal tissue were collected at surgery, RNA was extracted, and expression of 13 target genes was determined by quantitative polymerase chain reaction. Expression was normalized to GAPDH and POLR2A internal control genes. Expression relative to normal tissue (ddCT) and absolute expression (dCT) were calculated. Wilcoxon tests compared median expression with false discovery rate correction for multiple comparisons.

Results

Gene expression was similar in two gastric and seven duodenal tumors, and these were analyzed together. Like SBNETs (n = 63) and PNETs (n = 51), GDNETs showed significant overexpression compared with normal tissue of BRS3, GIPR, GRM1, GPR113, OPRK1, and SSTR2 (P < 0.05 for all). Of these, SSTR2 had the highest absolute expression in GDNETs (median dCT 4.0). Absolute expression of BRS3, GRM1, GPR113, and OPRK1 was significantly lower than SSTR2 in GDNETs (P < 0.05 for all), whereas expression of GIPR was similar to SSTR2 (median 4.3, P = 0.4).

Conclusions

As in SBNETs and PNETs, GIPR shows absolute expression close to SSTR2 but has greater overexpression relative to normal tissue (21.1 versus 3.5-fold overexpression). We conclude that GIPR could provide an improved signal-to-noise ratio for imaging versus SSTR2 and represents a promising novel therapeutic target in GDNETs.

Introduction

Duodenal neuroendocrine tumors constitute one of the rarest types of neuroendocrine tumors (NETs), with an annual incidence of 0.19 per 100,000 in the United States, representing approximately 4% of all NETs [1], [2]. Gastric neuroendocrine tumors have an incidence of 0.30 per 100,000, and their numbers have increased dramatically over time because of the proliferation of upper endoscopy and possibly the use of acid suppressive medications [1], [3], [4]. Although most gastric and duodenal neuroendocrine tumors (GDNETs) are small, amenable to endoscopic resection and rarely metastatic, a subpopulation exists of generally larger and more aggressive tumors requiring a more extensive staging evaluation, operative treatment, and often postoperative medical therapy [3].

Staging, preoperative planning, and medical treatment of other types of NETs exploit high expression of the somatostatin receptor in these tumors [5], [6]. Molecules such as octreotide, which binds principally to the somatostatin-receptor-type-2 (SSTR2), can decrease symptoms from hormone overproduction syndromes and reduce tumor progression in midgut NET patients [7]. Linking somatostatin analogs to radioligands such as ¹¹¹In or ⁶⁸Ga allows them to accumulate selectively at the tumor, permitting radiographic visualization of tumor tissues [8], [9], [10]. In peptide receptor radionuclide therapy, somatostatin analogs linked to higher-energy isotopes (⁹⁰Y or ¹⁷⁷Lu) can actually kill tumor cells [11]. Yet even with the success of these tests and therapies in some patients, not all NETs express somatostatin receptors and not all patients respond to octreotide [9], [12], [13], [14].

To build on the success of somatostatin-based NET treatments and respond to the dilemma of patients in whom they fail, our group used G protein–coupled receptor and exon expression microarrays to find new therapeutic targets, determining expression of 384 genes in a small number of initial tumor samples [15] and validating expression of a panel of 13 genes in over 100 SBNETs and PNETs [15], [16], [17]. In these studies, OPRK1 and OXTR in SBNETs and GIPR in both SBNETs and PNETs emerged as potentially useful receptors. These three genes displayed absolute expression similar to SSTR2, while having significantly higher expression in tumors relative to normal tissues. This suggested that imaging strategies directed at these receptors might display improved signal-to-background characteristics, and treatments might have fewer effects on noncancerous tissue.

In GDNETs, the optimal use of somatostatin-directed therapies is unclear. Because of GDNETs' rarity, most studies of somatostatin-based therapies do not include them or analyze them along with other tumor types [4]. To inform the use of peptide receptor–directed imaging and therapy in GDNETs and assess potential new therapeutic targets, we set out to determine expression levels of this 13-gene panel in the rare and poorly studied population of GDNETs and compared these results with our previous findings in SBNETs and PNETs.