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The clinical implications and biologic relevance of neurofilament expression in gastroenteropancreatic neuroendocrine neoplasms
Article first published online: 11 OCT 2011
Copyright © 2011 American Cancer Society
Volume 118, Issue 10, pages 2763–2775, 15 May 2012
How to Cite
Schimmack, S., Lawrence, B., Svejda, B., Alaimo, D., Schmitz-Winnenthal, H., Fischer, L., Büchler, M. W., Kidd, M. and Modlin, I. (2012), The clinical implications and biologic relevance of neurofilament expression in gastroenteropancreatic neuroendocrine neoplasms. Cancer, 118: 2763–2775. doi: 10.1002/cncr.26592
- Issue published online: 3 MAY 2012
- Article first published online: 11 OCT 2011
- Manuscript Accepted: 12 SEP 2011
- Manuscript Revised: 31 AUG 2011
- Manuscript Received: 8 JUL 2011
- BON pancreatic cell line;
- internexin alpha;
- neuroendocrine neoplasm;
- pancreatic neuroendocrine tumor
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.
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.
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).
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. Cancer 2011. © 2011 American Cancer Society.