This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakakura, E. K. Articles by Ball, D. W. Search for Related Content PubMed PubMed Citation Articles by Nakakura, E. K. Articles by Ball, D. W. Related Collections Endocrine Oncology

Regulation of Neuroendocrine Differentiation in Gastrointestinal Carcinoid Tumor Cells by Notch Signaling

Department of Surgery (E.K.N.), University of California, San Francisco, California 94115; The Sidney Kimmel Comprehensive Cancer Center (V.R.S., K.E.S., M.W.B., N.J., B.J.C., B.D.N., D.W.B.) and Departments of Medicine (E.C.H., D.W.B.), and Surgery (B.J.C.), The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231; and Department of Surgery (M.K., H.C.), University of Wisconsin Medical School, and the University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792

Address all correspondence and requests for reprints to: Eric K. Nakakura, 1600 Divisadero Street, Room A-724, San Francisco, California 94115. E-mail: NakakuraE{at}surgery.ucsf.edu.

Context: Gastrointestinal (GI) carcinoid tumors elaborate serotonin and other vasoactive substances, causing the carcinoid syndrome. Based on developmental biology data, we hypothesized that basic helix-loop-helix transcription factors, including achaete-scute complex homolog-like 1 (Ascl1)/hASH1, and the Notch signaling pathway might regulate the neuroendocrine phenotype in GI carcinoids.

Objective: The aim of this study was to evaluate expression of developmental transcription factors and Notch signaling components in GI carcinoids and model their interaction in a relevant GI carcinoid cell line.

Design: Fourteen GI carcinoid tumor specimens, five paired adjacent normal tissues, fetal tissues, and tumor cell lines were analyzed by RT-PCR and immunoblot. BON carcinoid cells were further analyzed after Notch overexpression for neuroendocrine marker expression, serotonin production, and growth.

Setting: The study was conducted in an academic referral center.

Patients or Other Participants: Deidentified archival pathology specimens were examined.

Results: Among a panel of six developmental transcription factors tested, only Ascl1 mRNA was overexpressed compared with surrounding normal tissue (seven of 10 GI carcinoid tumors and in BON cells, none of five normal tissues). Ascl1 protein was also expressed in four of four carcinoid tumors and BON cells). Notch pathway ligands, receptors, and downstream effectors were widely expressed in tumor and normal specimens. Overexpression of activated Notch1 in BON cells led to induction of the Notch effector hairy and enhancer of split 1 (Hes1), loss of Ascl1, reductions in neuron-specific enolase, synaptophysin, and chromogranin A, and most significantly, an 89% decrease in serotonin concentration and equivalent reductions in serotonin-reactive cells and repression of tryptophan hydroxylase 1 mRNA.

Conclusions: The Notch signaling pathway is a significant regulator of neuroendocrine differentiation and serotonin production in GI carcinoid tumors.

This article has been cited by other articles:

				Y.-C. Wang, E. Gallego-Arteche, G. Iezza, X. Yuan, M. R Matli, S.-P. Choo, M. B Zuraek, R. Gogia, F. C Lynn, M. S German, et al. Homeodomain transcription factor NKX2.2 functions in immature cells to control enteroendocrine differentiation and is expressed in gastrointestinal neuroendocrine tumors Endocr. Relat. Cancer, March 1, 2009; 16(1): 267 - 279. [Abstract] [Full Text] [PDF]

				E. Ferretti, E. Tosi, A. Po, A. Scipioni, R. Morisi, M. S. Espinola, D. Russo, C. Durante, M. Schlumberger, I. Screpanti, et al. Notch Signaling Is Involved in Expression of Thyrocyte Differentiation Markers and Is Down-Regulated in Thyroid Tumors J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 4080 - 4087. [Abstract] [Full Text] [PDF]

				L. Ning, R. Jaskula-Sztul, M. Kunnimalaiyaan, and H. Chen Suberoyl Bishydroxamic Acid Activates Notch1 Signaling and Suppresses Tumor Progression in an Animal Model of Medullary Thyroid Carcinoma Ann. Surg. Oncol., September 1, 2008; 15(9): 2600 - 2605. [Abstract] [Full Text] [PDF]

				Y. Arvidsson, E. Andersson, A. Bergstrom, M. K Andersson, G. Altiparmak, A.-C. Illerskog, H. Ahlman, D. Lamazhapova, and O. Nilsson Amyloid precursor-like protein 1 is differentially upregulated in neuroendocrine tumours of the gastrointestinal tract Endocr. Relat. Cancer, June 1, 2008; 15(2): 569 - 581. [Abstract] [Full Text] [PDF]

				L. Ning, D. Y. Greenblatt, M. Kunnimalaiyaan, and H. Chen Suberoyl Bis-Hydroxamic Acid Activates Notch-1 Signaling and Induces Apoptosis in Medullary Thyroid Carcinoma Cells Oncologist, February 1, 2008; 13(2): 98 - 104. [Abstract] [Full Text] [PDF]

				A Fratticci, F A Grieco, C Spilioti, F Giangaspero, L Ventura, V Esposito, M Piccirilli, A Santoro, A Gulino, G Cantore, et al. Differential expression of neurogenins and NeuroD1 in human pituitary tumours J. Endocrinol., September 1, 2007; 194(3): 475 - 484. [Abstract] [Full Text] [PDF]

				D. Y. Greenblatt, A. M. Vaccaro, R. Jaskula-Sztul, L. Ning, M. Haymart, M. Kunnimalaiyaan, and H. Chen Valproic Acid Activates Notch-1 Signaling and Regulates the Neuroendocrine Phenotype in Carcinoid Cancer Cells Oncologist, August 1, 2007; 12(8): 942 - 951. [Abstract] [Full Text] [PDF]

				M. Kunnimalaiyaan and H. Chen Tumor Suppressor Role of Notch-1 Signaling in Neuroendocrine Tumors Oncologist, May 1, 2007; 12(5): 535 - 542. [Abstract] [Full Text] [PDF]

				M. Kunnimalaiyaan, A. M. Vaccaro, M. A. Ndiaye, and H. Chen Inactivation of glycogen synthase kinase-3{beta}, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells Mol. Cancer Ther., March 1, 2007; 6(3): 1151 - 1158. [Abstract] [Full Text] [PDF]

				M. Kunnimalaiyaan, A. M. Vaccaro, M. A. Ndiaye, and H. Chen Overexpression of the NOTCH1 Intracellular Domain Inhibits Cell Proliferation and Alters the Neuroendocrine Phenotype of Medullary Thyroid Cancer Cells J. Biol. Chem., December 29, 2006; 281(52): 39819 - 39830. [Abstract] [Full Text] [PDF]