Aura D. Herrera-Martínez

The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features

BACKGROUNDnLung carcinoids (LCs) are rare tumors that comprise 1-5% of lung malignancies but represent 20-30% of neuroendocrine tumors. Their incidence is progressively increasing and a better characterization of these tumors is required. Alterations in somatostatin (SST)/cortistatin (CORT) and ghrelin systems have been associated to development/progression of various endocrine-related cancers, wherein they may become useful diagnostic, prognostic and therapeutic biomarkers.nnnOBJECTIVESnWe aimed to evaluate the expression levels of ghrelin and SST/CORT system components in LCs, as well as to explore their putative relationship with histological/clinical characteristics.nnnPATIENTS AND METHODSnAn observational retrospective study was performed; 75 LC patients with clinical/histological characteristics were included. Samples from 46 patients were processed to isolate mRNA from tumor and adjacent non-tumor region, and the expression levels of SST/CORT and ghrelin systems components, determined by quantitative-PCR, were compared to those of 7 normal lung tissues.nnnRESULTSnPatient cohort was characterized by mean age 53±15 years, 48% males, 34% with tobacco exposure; 71.4/28.6% typical/atypical carcinoids, 21.7% incidental tumors, 4.3% functioning tumors, 17.7% with metastasis. SST/CORT and ghrelin system components were expressed at variable levels in a high proportion of tumors, as well as in adjacent non-tumor tissues, while a lower proportion of normal lung samples also expressed these molecules. A gradation was observed from normal non-neoplastic lung tissues, non-tumor adjacent tissue and LCs, being SST, sst4, sst5, GHS-R1a and GHS-R1b overexpressed in tumor tissue compared to normal tissue. Importantly, several SST/CORT and ghrelin system components displayed significant correlations with relevant clinical parameters, such as necrosis, peritumoral and vascular invasion, or metastasis.nnnCONCLUSIONnAltogether, these data reveal a prominent, widespread expression of key SST/CORT/ghrelin system components in LCs, where they display clinical-histological correlations, which could provide novel, valuable markers for NET patient management.

Arterial Calcium Stimulation with Hepatic Venous Sampling in the Localization Diagnosis of Endogenous Hyperinsulinism

Objective. The aim of this study was to assess the utility of arterial calcium stimulation with hepatic venous sampling (ASVS) in the localization diagnosis of endogenous hyperinsulinism. Patients and Methods. A retrospective descriptive study was performed including patients with endogenous hyperinsulinism who underwent ASVS. The histopathological diagnosis in patients who underwent a surgical procedure was used as the reference for the statistical study of the accuracy of this technique. Results. 30 patients were included with endogenous hyperinsulinism and nonconclusive imaging diagnosis was included. ASVS was performed in all cases. Surgery was performed in 20 cases. Insulinoma was removed in 19 patients; the location of all cases was detected in the ASVS. All cases of endogenous hyperinsulinism had a positive result for the ASVS, with this association being statistically significant (χ 2 = 15.771; p < 0.001). A good and statistically significant agreement was obtained between histopathologic diagnosis and ASVS results (K = 0.518, p < 0.001). Conclusions. ASVS is a useful procedure in the localization diagnosis of endogenous hyperinsulinism undetected by other imaging tests. This technique allows the localization of intrapancreatic insulinomas and represents useful tool for the diagnosis and surgical management of these tumors.

Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors

PurposeGastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise a heterogeneous group of malignancies often presenting with metastasis at diagnosis and whose clinical outcome is difficult to predict. Somatostatin (SST) analogs (SSAs) provide a valuable pharmacological tool to palliate hormonal symptoms, and control progression in some NETs. However, many patients do not respond to SSAs or develop resistance, and there are many uncertainties regarding pathophysiology of SST and its receptors (sst1–sst5) in GEP-NETs.MethodsThe expression of SST system components in GEP-NETs was determined, compared with that of non-tumor adjacent and normal tissues and correlated with clinical and histological characteristics. Specifically, 58 patients with GEP-NETs and 14 normal samples were included. Cell viability in NET cell lines was determined in response to specific SSAs.ResultsNormal samples and non-tumor adjacent tissues presented a similar expression profile, with appreciable expression of sst2 and sst3, and a lower expression of the other receptors. In contrast, cortistatin, sst1, sst4, and sst5 were overexpressed in tumors, while sst3 and sst4 seemed overexpressed in less differentiated tumors. Some SST system components were related to vascular/nerve invasion and metastasis. In vitro, sst1 and sst3 agonists reduced viability in BON-1 cells, while they, similar to octreotide and pasireotide, increased viability in QGP-1 cells.ConclusionsThese results provide novel information on SST system pathophysiology in GEP-NETs, including relevant associations with clinical-histological parameters, which might help to better understand the intrinsic heterogeneity of NETs and to identify novel biomarkers and/or targets with potential prognostic and/or therapeutic value for GEP-NETs patients.

Type 2 diabetes in neuroendocrine tumors: are biguanides and statins part of the solution?

ContextnBiguanides and statins exert beneficial effects on various cancer types. Their precise effects and underlying molecular mechanisms are poorly understood.nnnMaterials and MethodsnWe analyzed the relationship between metabolic syndrome and histological, epidemiological, and prognosis variables in two cohorts of patients with neuroendocrine tumors (NETs): those with lung carcinoids (LCs; n = 81) and those with gastroenteropancreatic NET (GEP-NET; n = 100). Biguanide and statin antitumor effects were investigated by evaluating proliferation, migration, secretion, gene expression, and involved molecular pathways in BON1/QGP1 cell cultures.nnnResultsnPleura invasion was higher (LCs group; P < 0.05) and tumor diameter tended to be increased (GEP-NET group) in patients with type 2 diabetes (T2DM) than in those without. Somatostatin and ghrelin systems mRNA levels differed in tumor tissue of patients with T2DM taking metformin or not. Biguanides decreased proliferation rate in BON1/QGP1 cells; the effects of statins on proliferation rate depended on the statin and cell types, and time. Specifically, only simvastatin and atorvastatin decreased proliferation in BON1 cells, whereas all statins decreased proliferation rate in QGP1 cells. Metformin and simvastatin decreased migration capacity in BON1 cells; biguanides decreased serotonin secretion in BON1 cells. Phenformin increased apoptosis in BON1/QGP1 cells; simvastatin increased apoptosis in QGP1 cells. These antitumor effects likely involved altered expression of key genes related to cancer aggressiveness.nnnConclusionnA clear inhibitory effect of biguanides and statins was seen on NET-cell aggressiveness. Our results invite additional exploration of the potential therapeutic role of these drugs in treatment of patients with NETs.

Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Novel Potential Biomarker in Gastroenteropancreatic Neuroendocrine Tumors

Objectives: The association between the presence and alterations of the components of the ghrelin system and the development and progression of neuroendocrine tumors (NETs) is still controversial and remains unclear. Methods: Here, we systematically evaluated the expression levels (by quantitative‐PCR) of key ghrelin system components of in gastroenteropancreatic (GEP)‐NETs, as compared to non‐tumor adjacent (NTA; n = 42) and normal tissues (NT; n = 14). Then, we analyzed their putative associations with clinical‐histological characteristics. Results: The results indicate that ghrelin and its receptor GHSR1a are present in a high proportion of normal tissues, while the enzyme ghrelin‐O‐acyltransferase (GOAT) and the splicing variants In1‐ghrelin and GHSR1b were present in a lower proportion of normal tissues. In contrast, all ghrelin system components were present in a high proportion of tumor and NTA tissues. GOAT was significantly overexpressed (by quantitative‐PCR (qPCR)) in tumor samples compared to NTA, while a trend was found for ghrelin, In1‐ghrelin and GHSR1a. In addition, expression of these components displayed significant correlations with key clinical parameters. The marked overexpression of GOAT in tumor samples compared to NTA regions was confirmed by IHC, revealing that this enzyme is particularly overexpressed in gastrointestinal NETs, where it is directly correlated with tumor diameter. Conclusions: These results provide novel information on the presence and potential pathophysiological implications of the ghrelin system components in GEP‐NETs, wherein GOAT might represent a novel diagnostic biomarker.