Elevated sortilin expression discriminates functional from non-functional neuroendocrine tumors and enables therapeutic targeting.

A subset of neuroendocrine tumors (NETs) can cause an excessive secretion of hormones, neuropeptides, and biogenic amines into the bloodstream. These so-called functional NETs evoke a hormone-related disease and lead to several different syndromes, depending on the factors released. One of the most common functional syndromes, carcinoid syndrome, is characterized mainly by over-secretion of serotonin. However, what distinguishes functional from non-functional tumors on a molecular level remains unknown. Here, we demonstrate that the expression of sortilin, a widely expressed transmembrane receptor involved in intracellular protein sorting, is significantly increased in functional compared to non-functional NETs and thus can be used as a biomarker for functional NETs. Furthermore, using a cell line model of functional NETs, as well as organoids, we demonstrate that inhibition of sortilin reduces cellular serotonin concentrations and may therefore serve as a novel therapeutic target to treat patients with carcinoid syndrome.

Osteopontin is a prognostic circulating biomarker in patients with neuroendocrine neoplasms.

PURPOSE: Osteopontin (OPN), also called secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and which has been shown to be involved in tumorigenesis and metastasis in many malignancies. Its role in neuroendocrine neoplasms (NEN) remains to be established. The aim of the study was to analyze plasma concentrations of OPN in patients with NEN and to explore its diagnostic and prognostic value as a clinical biomarker. METHODS: OPN plasma concentrations were measured in a total of 38 patients with histologically proven NEN at three different time points during the course of disease and therapy (at the start of the study, after 3 and 12 months, respectively) as well as in healthy controls. Clinical and imaging data as well as concentrations of Chromogranin A (CgA) and Neuron Specific Enolase (NSE) were assessed. RESULTS: OPN levels were significantly higher in patients with NEN compared to healthy controls. High-grade tumors (grade 3) showed the highest OPN levels. OPN levels were neither different between male and female patients nor between different primary tumor sites. OPN correlated significantly with corresponding NSE levels, while there was no correlation with Chromogranin A. High OPN levels above a cutoff value of 200 ng/ml at initial analysis predicted a worsened prognosis with significantly shorter progression-free survival of patients with NEN, which also held true within the subgroup of well-differentiated G1/G2 tumors. CONCLUSION: Our data indicate that high baseline OPN levels in patients with NEN are predictive of an adverse outcome with shorter progression-free survival, even within the group of well differentiated G1/G2 tumors. Therefore, OPN may be used as a surrogate prognostic biomarker in patients with NEN.

Somatostatin receptor subtype-2-deficient mice with diet-induced obesity have hyperglycemia, nonfasting hyperglucagonemia, and decreased hepatic glycogen deposition.

Hypersecretion of glucagon contributes to abnormally increased hepatic glucose output in type 2 diabetes. Somatostatin (SST) inhibits murine glucagon secretion from isolated pancreatic islets via somatostatin receptor subtype-2 (sst2). Here, we characterize the role of sst2 in controlling glucose homeostasis in mice with diet-induced obesity. Sst2-deficient (sst2(-/-)) and control mice were fed high-fat diet for 14 wk, and the parameters of glucose homeostasis were monitored. Hepatic glycogen and lipid contents were quantified enzymatically and visualized histomorphologically. Enzymes regulating glycogen and lipid synthesis and breakdown were measured by real-time PCR and/or Western blot. Gluconeogenesis and glycogenolysis were determined from isolated primary hepatocytes and glucagon or insulin secretion from isolated pancreatic islets. Nonfasting glucose, glucagon, and fasting nonesterified fatty acids of sst2(-/-) mice were increased. Inhibition of glucagon secretion from sst2-deficient pancreatic islets by glucose or somatostatin was impaired. Insulin less potently reduced blood glucose concentration in sst2-deficient mice as compared with wild-type mice. Sst2-deficient mice had decreased nonfasting hepatic glycogen and lipid content. The activity/expression of enzymes controlling hepatic glycogen synthesis of sst2(-/-) mice was decreased, whereas enzymes facilitating glycogenolysis and lipolysis were increased. Somatostatin and an sst2-selective agonist decreased glucagon-induced glycogenolysis, without influencing de novo glucose production using cultured primary hepatocytes. This study demonstrates that ablation of sst2 leads to hyperglucagonemia. Increased glucagon concentration is associated with impaired glucose control in sst2(-/-) mice, resulting from decreased hepatic glucose storage, increased glycogen breakdown, and reduced lipid accumulation. Sst2 may constitute a therapeutic target to lower hyperglucagonemia in type 2 diabetes.