title: Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sampedro-Núñez
authors.affiliation: Department 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.
authors.forename: Raúl M
authors.initials: RM
authors.lastname: Luque
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ramos-Levi
authors.affiliation: Department 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.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Serrano-Somavilla
authors.affiliation: Department 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.
authors.forename: Alicia
authors.initials: A
authors.lastname: Villa-Osaba
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Adrados
authors.affiliation: Department 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.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ibáñez-Costa
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Pérez
authors.affiliation: IPSEN Bioscience, Cambridge, Massachusetts 02142, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Culler
authors.affiliation: Department of Endocrinology and Nutrition, Hospital Universitario de la Princesa, Instituto de Investigación Princesa, Universidad Autónoma de Madrid, Madrid 28006, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Marazuela
authors.affiliation: Department 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.
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042501:Angiogenic Proteins / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005455:Fluorescent Antibody Technique; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology*; D009367:Neoplasm Staging; D018358:Neuroendocrine Tumors / Q000235:genetics / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D012326:RNA Splicing / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017481:Receptors, Somatostatin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D042501:Angiogenic Proteins; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C094573:somatostatin receptor 5
keywords: angiogenesis; gastroenteropancreatic neuroendocrine tumors; neuroendocrine tumors; sst5TMD4; sst5TMD5