The impact of SST2 trafficking and signaling in the treatment of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (Pan-NETs), are heterogeneous neoplasms, whose incidence and prevalence are increasing worldwide. Pan-NETs are characterized by the expression of somatostatin receptors (SSTs). In particular, SST2 is the most widely distributed SST in NETs, thus representing the main molecular target for somatostatin analogs (SSAs). SSAs are currently approved for the treatment of well-differentiated NETs, and radionuclide-labeled SSAs are used for diagnostic and treatment purposes. SSAs, by binding to SSTs, have been shown to inhibit hormone secretion and thus provide control of hypersecretion symptoms, when present, and inhibit tumor proliferation. After SSA binding to SST2, the fate of the receptor is determined by trafficking mechanisms, crucial for the response to endogenous or pharmacological ligands. Although SST2 acts mostly through G protein-dependent mechanism, receptor-ligand complex endocytosis and receptor trafficking further regulate its function. SST2 mediates the decrease of hormone secretion via a G protein-dependent mechanism, culminating with the inhibition of adenylyl cyclase and calcium channels; it also inhibits cell proliferation and increases apoptosis through the modulation of protein tyrosine phosphatases. Moreover, SST2 inhibits angiogenesis and cell migration. In this respect, the cross-talk between SST2 and its interacting proteins, including Filamin A (FLNA) and aryl hydrocarbon receptor-interacting protein (AIP), plays a crucial role for SST2 signaling and responsiveness to SSAs. This review will focus on recent studies from our and other groups that have investigated the trafficking and signaling of SST2 in Pan-NETs, in order to provide insights into the mechanisms underlying tumor responsiveness to pharmacological treatments.

Secondary hyperparathyroidism and thoracic vertebral fractures in heart failure middle-aged patients: a 3-year prospective study.

PURPOSE: Vertebral fractures (VFs) were described in elderly patients with heart failure (HF) whereas their prevalence and determinants in younger HF patients are still unknown. This study aimed at assessing whether secondary hyperparathyroidism (SHPT) may influence the risk of VFs in middle-aged patients with HF. METHODS: 84 patients (44 males, median age 48.5 years, range 43-65) with HF were prospectively evaluated at the baseline and after 36-month follow-up for bone mineral density (BMD) and VFs by quantitative morphometry on chest X-rays. Serum PTH, calcium, 25-hydroxyvitamin D and 24-h-urinary calcium were evaluated at the baseline and every 6-12 months during the study period. RESULTS: At baseline, SHPT, hypovitaminosis D and VFs were found in 43 patients (51.2%), 73 patients (86.9%) and 29 patients (34.5%), respectively. SHPT was associated with VFs at baseline [inverse probability-weighted (ipw) odds ratio (OR) 12.2, p < 0.001]. Patients were treated with vitamin D3 alone (56%), vitamin D3 plus calcium carbonate (21.4%), calcitriol alone (4.8%), bisphosphonates plus vitamin D3 (8.3%) or a combination of bisphosphonates, vitamin D3 and calcium carbonate (9.5%). At the end of follow-up, hypovitaminosis D was corrected in all patients, whereas 19/84 patients (22.6%) had persistent SHPT. During the follow-up, 16 patients developed incident VFs which resulted to be associated with baseline SHPT (ipw OR 55.7, p < 0.001), even after adjusting from BMD change from baseline to follow-up (ipw OR 46.4, p < 0.001). CONCLUSIONS: This study provides a first evidence that SHPT may be a risk factor for VFs in middle-aged patients with HF.

A novel insight into the anticancer mechanism of metformin in pancreatic neuroendocrine tumor cells.

The antidiabetic drug metformin displays anticancer properties in several neoplasms. In pituitary NETs, aryl hydrocarbon receptor-interacting protein (AIP) is up-regulated by the somatostatin analog octreotide. Metformin inhibited QGP-1 cell proliferation in a dose- and time-dependent manner, at concentrations similar to those achievable in treated patients (-31 ± 12%, p < 0.05 vs basal at 100 µM). Moreover, metformin decreased pancreatic neuroendocrine tumors (PAN-NETs) cell proliferation (-62 ± 15%, p < 0.0001 vs basal at 10 mM), without any additive effect when combined with octreotide. Both octreotide and metformin induced AIP up-regulation. AIP silencing abolished the reduction of mTOR phosphorylation induced by metformin and octreotide. Moreover, metformin decreased HSP70, increased Zac1 and AhR expression; these effects were abolished in AIP silenced QGP-1 cells. In conclusion, metformin acts as an anticancer agent in PAN-NET cells, its activity is mediated by AIP and its interacting proteins. These findings provide a novel insight into the antitumorigenic mechanism of metformin.