Overexpression of Membrane Proteins in Primary and Metastatic Gastrointestinal Neuroendocrine Tumors

Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Annals of Surgical Oncology (Impact Factor: 3.93). 12/2013; 20(Suppl 3):S739-46. DOI: 10.1245/s10434-013-3318-6
Source: PubMed


Small bowel and pancreatic neuroendocrine tumors (SBNETs and PNETs) are rare tumors whose incidence is increasing. Drugs targeting the somatostatin receptor are beneficial in these tumors. To identify additional cell-surface targets, we recently found receptors and membrane proteins with gene expression significantly different from adjacent normal tissues in a small number of primary SBNETs and PNETs. We set out to validate these expression differences in a large group of primary neuroendocrine tumors and to determine whether they are present in corresponding liver and lymph node metastases.
Primary SBNETs and PNETs, normal tissue, nodal, and liver metastases were collected and mRNA expression of six target genes was determined by quantitative PCR. Expression was normalized to GAPDH and POLR2A internal controls, and differences as compared to normal tissue were assessed by Welch's t test.
Gene expression was determined in 45 primary PNETs with 20 nodal and 17 liver metastases, and 51 SBNETs with 50 nodal and 29 liver metastases. Compared to normal tissue, the oxytocin receptor (OXTR) showed significant overexpression in both primary and metastatic SBNETs and PNETs. Significant overexpression was observed for MUC13 and MEP1B in PNET primary tumors, and for GPR113 in primary SBNETs and their metastases. SCTR and ADORA1 were significantly underexpressed in PNETs and their metastases. OXTR protein expression was confirmed by immunohistochemistry.
OXTR is significantly overexpressed relative to normal tissue in primary SBNETs and PNETs, and this overexpression is present in their liver and lymph node metastases, making OXTR a promising target for imaging and therapeutic interventions.

Download full-text


Available from: Scott K Sherman, Mar 06, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: This article reviews translational research in endocrine surgery, with a focus on disorders of the thyroid, parathyroids, adrenals, and endocrine pancreas. Discovery of genes responsible for heritable endocrine cancer syndromes has increased knowledge of the causes and mechanisms of endocrine cancer and has refined surgical treatment options. Knowledge of mutations in sporadic cancer has led to rapid progress in small-molecule kinase inhibitor strategies. These breakthroughs and their influence on current therapy are discussed to provide surgeons with an overview of the basic science research currently creating new clinical treatments and improving patient care.
    No preview · Article · Oct 2013 · Surgical Oncology Clinics of North America
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ligands binding the somatostatin receptor type 2 (SSTR2) are useful for imaging and treatment of neuroendocrine tumors (NETs), but not all tumors express high levels of these receptors. The aim of this study was to evaluate gene expression of new therapeutic targets in NETs relative to SSTR2. RNA was extracted from 103 primary small bowel and pancreatic NETs, matched normal tissue, and 123 metastases. Expression of 12 candidate genes was measured by quantitative polymerase chain reaction normalized to internal controls; candidate gene expression was compared with SSTR2. Relative to normal tissue, primary NET expression of SSTR2, GPR98, BRS3, GIPR, GRM1, and OPRK1 were increased by 3, 8, 13, 13, 17, and 20-fold, respectively. Similar changes were found in metastases. Although most candidate genes showed lesser absolute expressions than SSTR2, absolute GIPR expression was closest to SSTR2 (mean dCT 3.6 vs 2.7, P = .01). Absolute OPRK1 and OXTR expression varied greatly by primary tumor type and was close to SSTR2 in small bowel NETs but not pancreatic NETs. Compared with the current treatment standard SSTR2, GIPR has only somewhat lesser absolute gene expression in tumor tissue but much lesser expression in normal tissue, making it a promising new target for NET imaging and therapy.
    Full-text · Article · Dec 2013 · Surgery
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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]). 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. 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). 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.
    Full-text · Article · Jan 2014 · Journal of Surgical Research
Show more