This work has received the following grants:
Proyectos de Investigación en Salud (FIS) PI13-01414,
and PIE-0041 (funded by Instituto de Salud Carlos III)
and S2011/BMD-2328 TIRONET (funded by Comunidad
de Madrid) (to MM). BIO-0139, CTS-5051, CTS-1406,
PI-0369-2012, BFU2010-19300, BFU2013-43282-R,
PI13/00651, CIBERobn and Ayuda Merck Serono 2013
(to RML and JPC). Fellowship CTS-5051 (to AIC). “Sara
Borrell” program CD11/00276 (to MDG). CIBER is an
initiative of Instituto de Salud Carlos III, Ministerio de
Sanidad, Servicios Sociales e Igualdad, Spai

Albini

Augustin

Bagnoli

Bruns

Buchan

Caplin

Castaño

Condeelis

Davis-Smyth

Del Tacca

Evans

Ferrara

Florio

Gadelha

Grabowski

Gress

Halperin

Held-Feindt

Hofland

Holst

Jones

Kono

Lang

Lupp

Marazuela

Martinez

McNicol

Oberg

Olsen

Pyronnet

Rindi

Rinke

Rougier

Schally

Schettini

Scoazec

Solcia

Stalla

Tacca

Thanos

Thompson

Vidal

Wiedenmann

Yalcin

Zatelli

Oncotarget

Gastroenteropancreatic 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. We 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. sst1 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. sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs.S

Sampedro-Nuñez, Miguel

Luque, Raul M

Ramos-Levi, Ana M

Gahete, Manuel D

Serrano-Somavilla, Ana

Villa-Osaba, Alicia

Adrados, Magdalena

Ibañez-Costa, Alejandro

Martin-Perez, Elena

Culler, Michael D

Marazuela, Monica

Castaño, Justo P

RISalud-ANDALUCÍA

Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors.

Miguel Sampedro-Núñez

Raúl M. Luque

Ana M. Ramos-Levi

Manuel D. Gahete

Ana Serrano-Somavilla

Alicia Villa-Osaba

Magdalena Adrados

Alejandro Ibáñez-Costa

Elena Martín-Pérez

Michael D. Culler

Mónica Marazuela

Justo P. Castaño

Crossref

Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

Purpose: Gastroenteropancreatic 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 Design: We 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. Results: sst1 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. Conclusions: sst5TMD4 is overexpressed in GEP-NETs and is associated to enhanced aggressiveness, suggesting its potential value as biomarker and target in GEP-NETs.This work has received the following grants: Proyectos de Investigación en Salud (FIS) PI13-01414, and PIE-0041 (funded by Instituto de Salud Carlos III) and S2011/BMD-2328 TIRONET (funded by Comunidad de Madrid) (to MM). BIO-0139, CTS-5051, CTS-1406, PI-0369-2012, BFU2010-19300, BFU2013-43282-R, PI13/00651, CIBERobn and Ayuda Merck Serono 2013 (to RML and JPC). Fellowship CTS-5051 (to AIC). “Sara Borrell” program CD11/00276 (to MDG

Sampedro Núñez,  Miguel Antonio

Luque, Raúl M.

Ramos-Levi, Ana M.

Gahete, Manuel D.

Ibáñez-Costa, Alejandro

Martín Pérez, María Elena

Culler, Michael D.

Marazuela Azpiroz, Mónica

Castaño, Justo P.

Biblos-e Archivo

Gastroenteropancreatic 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

Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors

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