Association for Academic SurgeryGIPR expression in gastric and duodenal neuroendocrine tumors
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.
Section snippets
Patients and clinical data
Patients undergoing surgery for abdominal NETs at a single center since 2005 were enrolled under an Institutional Review Board–approved protocol with full informed consent. Clinical and pathologic information for these patients was reviewed and included in the Iowa Neuroendocrine Tumor Registry Database [18]. Tumor and adjacent normal tissues were collected at the time of surgery and maintained in RNALater solution (Life Technologies, Grand Island, NY). GDNETs included NETs of the stomach and
Patient and tumor characteristics
Patients with gastric (n = 2) and duodenal (n = 7) NETs were included, and results compared with patients with SBNETs (n = 63) and PNETs (n = 51). Gene expression in the gastric NETs was found to be similar to that in duodenal tumors, and these were analyzed together (GDNETs, n = 9). Median age at surgery for GDNET patients was 57.3 (range 52.6–70.9). Median progression-free survival and overall survival were not yet reached. Preoperative laboratory values were available for most patients. The
Discussion
GDNETs that require operative treatment are a rare subset of all GDNETs for which optimal management remains uncertain. The present study demonstrates that GDNETs express SSTR2 at levels similar to SBNETs and PNETs, supporting the potential efficacy of somatostatin receptor–directed diagnostics and therapies in these tumors. That GDNETs also highly express GIPR, but with greater overexpression compared with background tissues, suggests that as in SBNETs and PNETs, GIPR is a potential target for
Acknowledgment
The authors gratefully acknowledge their patients for their participation.
Supported by National Institutes of Health 5T32#CA148062-03 (S.K.S., J.E.M., J.C.C.).
None of the authors has any potential conflicts of interest to disclose.
Author Contributions: Concept and design: S.K.S., J.C.C., M.S.O., T.M.O., J.R.H.; Analysis and Interpretation: S.K.S.; Data Collection: S.K.S., J.E.M., J.C.C., D.W.; Writing: S.K.S., J.E.M.; Critical Revision: M.S.O., T.M.O., J.R.H.; Obtaining Funding: J.R.H.
References (37)
- et al.
Gastric and duodenal neuroendocrine tumours
Best Pract Res Clin Gastroenterol
(2012) - et al.
Somatostatin receptor subtype expression in human tumors
Ann Oncol
(2001) - et al.
Gastroenteropancreatic neuroendocrine tumours
Lancet Oncol
(2008) - et al.
Translational research in endocrine surgery
Surg Oncol Clin N Am
(2013) - et al.
Differentiation of small bowel and pancreatic neuroendocrine tumors by gene-expression profiling
Surgery
(2012) - et al.
Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors
Surgery
(2013) - et al.
Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study
Lancet
(2011) - et al.
Therapeutic potential for GIP receptor agonists and antagonists
Best Pract Res Clin Endocrinol Metab
(2009) - et al.
Glucose-dependent insulinotropic polypeptide stimulates the proliferation of colorectal cancer cells
Regul Pept
(2010) - et al.
Prolonged GIP receptor activation using stable mini-PEGylated GIP improves glucose homeostasis and beta-cell function in age-related glucose intolerance
Peptides
(2009)
Gene expression in neuroendocrine tumor liver metastases accurately distinguishes between pancreas and small bowel primary tumors
J Am Coll Surg
One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States
J Clin Oncol
Clinical Outcomes for neuroendocrine tumors of the duodenum and ampulla of Vater: a population-based study
J Gastrointest Surg
ENETS Consensus Guidelines for the management of patients with gastroduodenal neoplasms
Neuroendocrinology
Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group
J Clin Oncol
Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients
Eur J Nucl Med
Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors
Endocr Relat Cancer
The value of preoperative imaging in small bowel neuroendocrine tumors
Ann Surg Oncol
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Presented at the 9th Annual Academic Surgical Congress; February 4, 2014; San Diego, California.