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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Miguel Sampedro-Núñez1,*, Raúl M. Luque2,*, Ana M. Ramos-Levi1,*, Manuel D. Gahete2, Ana Serrano-Somavilla1, Alicia Villa-Osaba2, Magdalena Adrados1, Alejandro Ibáñez-Costa2, Elena Martín-Pérez1, Michael D. Culler3, Mónica Marazuela1,*, Justo P. Castaño2,*
1Department of Endocrinology and Nutrition, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain
2Department of Cell Biology, Physiology and Immunology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia, and CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba 14014, Spain
3IPSEN Bioscience, Cambridge, Massachusetts 02142, USA
*These authors contributed equally to this work
Justo P. Castaño, e-mail: firstname.lastname@example.org
Raúl M. Luque, e-mail: email@example.com
Monica Marazuela, e-mail: firstname.lastname@example.org
Keywords: neuroendocrine tumors, sst5TMD4, sst5TMD5, angiogenesis, gastroenteropancreatic neuroendocrine tumors
Received: July 31, 2015 Accepted: November 21, 2015 Published: December 11, 2015
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.
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