Abstract
PurposeGastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare and heterogeneous tumors, and their biological behavior is not well known. We studied the presence and potential functional roles of somatostatin receptors (sst1-5), focusing particularly on the truncated variants (sst5TMD4, sst5TMD5) and on their relationships with the angiogenic system (Ang/Tie-2 and VEGF) in human GEP-NETs.Experimental DesignWe evaluated 42 tumor tissue samples (26 primary/16 metastatic) from 26 patients with GEP-NETs, and 30 non-tumoral tissues (26 from adjacent non-tumor regions and 4 from normal controls) from a single center. Expression of sst1-5, sst5TMD4, sst5TMD5, Ang1-2, Tie-2 and VEGF was analyzed using real-time qPCR, immunofluorescence and immunohistochemistry. Expression levels were associated with tumor characteristics and clinical outcomes. Functional role of sst5TMD4 was analyzed in GEP-NET cell lines.Resultssst1 exhibited the highest expression in GEP-NET, whilst sst2 was the most frequently observed sst-subtype (90.2%). Expression levels of sst1, sst2, sst3, sst5TMD4, and sst5TMD5 were significantly higher in tumor tissues compared to their adjacent non-tumoral tissue. Lymph-node metastases expressed higher levels of sst5TMD4 than in its corresponding primary tumor tissue. sst5TMD4 was also significantly higher in intestinal tumor tissues from patients with residual disease of intestinal origin compared to those with non-residual disease. Functional assays demonstrated that the presence of sst5TMD4 was associated to enhanced malignant features in GEP-NET cells. Angiogenic markers correlated positively with sst5TMD4, which was confirmed by immunohistochemical/fluorescence studies.Conclusionssst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs.
Highlights
Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms derived from enterochromaffin epithelial cells, which retain many structural and functional features of normal endocrine cells, including production of chromogranin A (CgA), synaptophysin, and other peptides [1]
A total of 15 patients presented with metastasis, the majority of them in regional lymph nodes and/or liver
Pre-surgical 5-hydroxy-indoleacetic acid was available in 8 patients, with a mean value of 17.2 ± 17.6 mg/24 h (median 7.8 (2–42) mg/24 h; reference range 2–10 mg/24 h)
Summary
Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms derived from enterochromaffin epithelial cells, which retain many structural and functional features of normal endocrine cells, including production of chromogranin A (CgA), synaptophysin, and other peptides [1] The majority of these tumors are of gastro-entero-pancreatic origin (GEP-NET) and, they were initially believed to be uncommon neoplasms, their incidence and prevalence is increasing, and because of improved imaging techniques [2]. The first therapeutic option for GEP-NETs is the surgical approach, complete cure is not possible in many cases, and development of systemic medical treatments has gained scientific and clinical interest over the past recent years In this setting, synthetic somatostatin analogues (SSAs) have emerged as a successful tool for the management of neuroendocrine diseases [4, 5]. They exert antitumor effects; this was confirmed by the results of the PROMID study [6], which reported a significant increase in time to tumor progression in functionally active and inactive tumors; and in a more evident way, in the recent CLARINET study, which further reported an increase in median progression-free survival in SSA-treated patients [7]
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