title: The clinical implications and biologic relevance of neurofilament expression in gastroenteropancreatic neuroendocrine neoplasms.
abstract: BACKGROUND
  Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) exhibit widely divergent behavior, limited biologic information (apart from Ki-67) is available to characterize malignancy. Therefore, the identification of alternative biomarkers is a key unmet need. Given the role of internexin alpha (INA) in neuronal development, the authors assessed its function in neuroendocrine cell systems and the clinical implications of its expression as a GEP-NEN biomarker.
  
  
  METHODS
  Functional assays were undertaken to investigate the mechanistic role of INA in the pancreatic BON cell line. Expression levels of INA were investigated in 50 pancreatic NENs (43 primaries, 7 metastases), 43 small intestinal NENs (25 primaries, 18 metastases), normal pancreas (n = 10), small intestinal mucosa (n = 16), normal enterochromaffin (EC) cells (n = 9), mouse xenografts (n = 4) and NEN cell lines (n = 6) using quantitative polymerase chain reaction, Western blot, and immunostaining analyses.
  
  
  RESULTS
  In BON cells, decreased levels of INA messenger RNA and protein were associated with the inhibition of both proliferation and mitogen-activated protein kinase (MAPK) signaling. INA was not expressed in normal neuroendocrine cells but was overexpressed (from 2-fold to 42-fold) in NEN cell lines and murine xenografts. In pancreatic NENs, INA was overexpressed compared with pancreatic adenocarcinomas and normal pancreas (27-fold [P = .0001], and 9-fold [P = .02], respectively). INA transcripts were correlated positively with Ki-67 (correlation coefficient [r] = 0.5; P < .0001) and chromogranin A (r = 0.59; P < .0001). INA distinguished between primary tumors and metastases (P = .02), and its expression was correlated with tumor size, infiltration, and grade (P < .05).
  
  
  CONCLUSIONS
  INA is a novel NEN biomarker, and its expression was associated with MAPK signaling and proliferation. In clinical samples, elevated INA was correlated with Ki-67 and identified malignancy. INA may provide additional biologic information relevant to delineation of both pancreatic NEN tumor phenotypes and clinical behavior.
authors: Department of Gastroenterological Surgery, Yale University School of Medicine, New Haven, CT, USA.
authors: Simon
authors: S
authors: Schimmack
authors: Ben
authors: B
authors: Lawrence
authors: Bernhard
authors: B
authors: Svejda
authors: Daniele
authors: D
authors: Alaimo
authors: Hubertus
authors: H
authors: Schmitz-Winnenthal
authors: Lars
authors: L
authors: Fischer
authors: Markus W
authors: MW
authors: Büchler
authors: Mark
authors: M
authors: Kidd
authors: Irvin
authors: I
authors: Modlin
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D005770:Gastrointestinal Neoplasms / Q000737:chemistry* / Q000473:pathology; D006801:Humans; D007381:Intermediate Filament Proteins / Q000032:analysis* / Q000502:physiology; D051379:Mice; D018358:Neuroendocrine Tumors / Q000737:chemistry* / Q000473:pathology; D016900:Neurofilament Proteins / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D010179:Pancreas / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D007381:Intermediate Filament Proteins; D016900:Neurofilament Proteins; C046643:alpha-internexin; C044882:neurofilament protein L; C051774:neurofilament protein H; C061195:neurofilament protein M