1: Cancer. 1997 Aug 15;80(4):668-75.
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Oncogene expression in gastroenteropancreatic neuroendocrine tumors: implications for pathogenesis.
Wang DG, Johnston CF, Buchanan KD.
Division of Metabolism and Endocrinology, School of Clinical Medicine, The Queen's University of Belfast, United Kingdom.
BACKGROUND: Neuroendocrine tumors of the gastroenteropancreatic system include pancreatic islet cell and carcinoid tumors. These tumors comprise a functionally and biologically heterogeneous group of neoplasms that rarely show reliable histopathologic signs of malignancy. No etiologic factors are proven to be associated with them, and their exact ontogeny and carcinogenesis remain unknown. METHODS: Monoclonal antibodies were employed, along with microwave antigen retrieval and the avidin-biotin immunohistochemical method, to investigate the expression of c-myc, bcl-2, c-erb B-2, c-erb B-3, c-jun, and proliferating cell nuclear antigen (PCNA) in a retrospective series of 116 primary gastroenteropancreatic neuroendocrine tumors (GPNTs). The authors attempted to correlate this expression with the clinicopathologic outcome of the disease. RESULTS: Immunoreactivities for c-myc, bcl-2, c-erb B-2, c-erb B-3, and c-jun were detected in 100%, 45%, 24%, 7%, and 24% of pancreatic neuroendocrine tumors (PNTs), respectively. In carcinoid tumors, immunoreactivities were detected for c-myc (63%), bcl-2 (28%), c-erb B-2 (31%), c-erb B-3 (6%), and c-jun (23%). There were significantly higher incidences of c-myc, bcl-2, and c-erb B-2 immunoreactivities in carcinoid tumors of the rectum than in those of the appendix, and significantly higher incidences of bcl-2 and c-jun immunoreactivities in carcinoid tumors of the bronchus than in those of the appendix. Incidence of PCNA immunoreactivity was significantly higher in malignant than in benign PNTs and also significantly higher in carcinoid tumors of the jejunum and ileum than in those of the appendix. CONCLUSIONS: The oncogenes c-myc, bcl-2, c-erb B-2, and c-jun are frequently expressed in human GPNTs. The expression of these oncogenes may represent pathogenic events in the generation, malignant transformation, and progression of GPNTs. The immunohistochemical evaluation of cell kinetics in GPNTs by PCNA might be a useful adjunct to conventional diagnostic procedures.
PMID: 9264349 [PubMed - indexed for MEDLINE]
1: Eur J Clin Invest. 1998 Dec;28(12):1038-49.
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Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours.
Wulbrand U, Wied M, Zofel P, Goke B, Arnold R, Fehmann H.
Philipps-University Marburg, Germany.
wulbranu@post.med.uni-marburg.de
BACKGROUND: Human gastroenteropancreatic neuroendocrine tumours are functionally and biologically heterogeneous, but their exact growth factor receptor expression pattern, important for onco- and carcinogenesis, remains unknown. METHODS: This study searched for the mRNA expression pattern of six tyrosine- and serine/threonine kinase receptors [hepatocyte growth factor (HGFR), fibroblast growth factor (FGFR), epidermal growth factor (EGFR), insulin-like growth factor (IGF)-1R, transforming growth factor (TGF)-betaR1, TGF-betaR2] together with the five somatostatin receptors in human gastroenteropancreatic neuroendocrine tumours (gastrinomas, insulinomas, tumours with carcinoid syndrome, functionally inactive neuroendocrine tumours) using reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: EGF receptor was expressed almost exclusively in gastrinomas. Among the four tumour subtypes, expression frequencies of the somatostatin receptors 1 and 5, HGF-, IGF-1-, TGF-betaR1, TGF-betaR2 and the EGF-receptor varied significantly. CONCLUSIONS: In spite of the common cellular origin of these tumours, differences in growth factor receptor expression suggest the existence of different pathways during tumour subtype development.
PMID: 9893017 [PubMed - indexed for MEDLINE
1: Mod Pathol. 2005 Oct;18(10):1329-35.
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Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas.
Papouchado B, Erickson LA, Rohlinger AL, Hobday TJ, Erlichman C, Ames MM, Lloyd RV.
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of many tumors. To analyze the expression of EGFR and activated EGFR in well-differentiated neuroendocrine carcinomas including primary and metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors (PET), we examined 58 gastrointestinal carcinoid tumors and 48 PET using immunohistochemistry, Western blotting, and RT-PCR. EGFR and activated EGFR (P-EGFR) were expressed by both gastrointestinal carcinoids and PET in primary and metastatic tumors, although a higher percentage of gastrointestinal carcinoid tumors expressed EGFR and activated EGFR. Western blotting detected a 170 kDa band for both EGFR and activated EGFR in three primary carcinoid tumors and two metastatic carcinoid tumors to the liver. RT-PCR analysis confirmed the expression of EGFR mRNA in both primary and metastatic carcinoid tumors. Patients with activated EGFR expression in their primary PET had a significantly worse prognosis compared to those who did not express activated-EGFR (P = 0.043). These results indicate that gastrointestinal carcinoid tumors as well as PET express EGFR and activated EGFR, and that expression is more common in gastrointestinal carcinoid tumors compared to pancreatic endocrine tumors. These findings implicate the EGFR and P-EGFR signal transduction pathway in the pathogenesis of these neuroendocrine tumors and suggest that targeted therapy directed against the EGFR tyrosine kinase domain may be a useful therapeutic approach in patients with unresectable metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors.
PMID: 15920550 [PubMed - indexed for MEDLINE]
1: Eur J Clin Invest. 2000 Aug;30(8):729-39.
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mRNA expression patterns of insulin-like growth factor system components in human neuroendocrine tumours.
Wulbrand U, Remmert G, Zofel P, Wied M, Arnold R, Fehmann HC.
Department of Internal Medicine, Philipps-University Marburg, Germany.
ulrich.wulbrand@uni-tuebingen.de
BACKGROUND: Insulin-like growth factors (IGF) and their corresponding receptors and binding proteins are important in carcinogenesis for several tumours, but their expression pattern in the functionally and biologically heterogeneous human neuroendocrine tumours of the gastroenteropancreatic tract is largely unknown. MATERIALS AND METHODS: This study searched for the mRNA expression patterns of components of the IGF system: IGF-1 and IGF-2, IGF receptors 1 and 2 (IGF-1R, IGF-2R), IGF-binding proteins 1-6 (IGFBP1-6)) in the most frequent human gastroenteropancreatic neuroendocrine tumours (gastrinomas, insulinomas, tumours associated with carcinoid syndrome and functionally inactive tumours) employing reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS: In the 37 tumour samples analysed (nine gastrinomas, 10 insulinomas, nine tumours associated with carcinoid syndrome and nine functionally inactive tumours) IGFBP-2 was found in all tumour samples while the IGFBP-1 was expressed only at low frequency (10-22%) among the four tumour types. The IGF-2R was predominantly expressed in gastrinomas. Among the four tumour types the expression of IGF-1R, IGF-2R and IGFBP-6 varied significantly. In addition, 12 pairs of significantly coexpressed IGF system components were detected (IGF-1 <--> IGF-1R, IGF-1 <--> IGF-2R, IGF-1 <--> IGFBP-3, IGF-1 <--> IGFBP-6, IGFBP-3 <--> IGF-1R, IGFBP-6 <--> IGF-1R, IGFBP-1 <--> IGF-2R, IGFBP-3 <--> IGF-2R, IGFBP-5 <--> IGF-2R, IGFBP-3 <--> IGFBP-5, IGFBP-3 <--> IGFBP-6, IGFBP-5 <--> IGFBP-6). CONCLUSIONS: The described differences of the expression patterns of the IGF system components in neuroendocrine tumour subtypes suggest tumour type-dependent different pathways in tumour growth control by IGF system components.
PMID: 10964166 [PubMed - indexed for MEDLINE]
1: Neuroendocrinology. 2005;81(1):1-9. Epub 2005 Apr 4.
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Nuclear survivin is a powerful novel prognostic marker in gastroenteropancreatic neuroendocrine tumor disease.
Grabowski P, Griss S, Arnold CN, Horsch D, Goke R, Arnold R, Heine B, Stein H, Zeitz M, Scherubl H.
Medical Clinic I, Gastroenterology/Infectious Diseases/Rheumatology, Universitatsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Gastroenteropancreatic neuroendocrine tumors represent a heterogeneous tumor entity. The growth pattern ranges from very slowly to fast growing, aggressive types of tumors. Survivin, a member of the family of apoptosis inhibitors, is a bifunctional protein that suppresses apoptosis and regulates cell division. In this study we determined the prognostic value of survivin in this tumor entity. Tumor specimens from 104 patients (38 foregut, 53 midgut, 13 hindgut) were studied immunohistochemically for cytoplasmic and nuclear survivin expression as well as for ki-67 antigen expression. 5-year-follow-up was complete in 89 patients. 29 patients with localized, well-differentiated gastroenteropancreatic neuroendocrine tumors (WDET, WHO class 1) had been curatively treated by surgical or endoscopic tumor resection. 50 patients suffered from well-differentiated endocrine carcinomas (WDEC, WHO class 2), 10 patients were diagnosed with poorly differentiated neuroendocrine carcinomas (PDEC, WHO class 3). Survivin expression was correlated with survival for the 50 patients with metastatic WDEC disease. All 29 WDETs were negative for nuclear survivin, whereas all 10 PDECs stained positive for nuclear survivin. In the 50 patients with metastatic WDECs, 5/50 (10%) tumors were nuclear survivin positive. Those 5 patients had a statistically significant worse prognosis (survival of 41 vs. 103 months, p=0.01). ki-67 was not a prognostic factor in this subgroup of patients. Nuclear survivin expression thus appears to be upregulated during progression of gastroenteropancreatic neuroendocrine tumors. The analysis of nuclear survivin expression identifies subgroups in metastatic disease (WHO class 2) with good (survivin-) or with less favorable prognosis (survivin+). We propose that the determination of nuclear survivin expression could be used to individualize therapeutic strategies in this tumor entity in the future. Copyright (c) 2005 S. Karger AG, Basel.
PMID: 15809513 [PubMed - indexed for MEDLINE]
Int J Cancer. 1997 Jun 20;74(3):270-4.
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Expression of a breast-cancer-associated protein (pS2) in human neuro-endocrine tumours.
Wang DG, Johnston CF, Liu WH, Sloan JM, Buchanan KD.
Metabolism and Endocrinology Division, School of Clinical Medicine, The Queen's University of Belfast, N. Ireland, UK.
d.wang@qub.ac.uk
pS2 protein expression has been demonstrated in a range of malignant tissues in an oestrogen-independent pathway. Recently, it has been demonstrated that pS2, in prostate cancer, is closely associated with neuro-endocrine differentiation. In the present study, we have analyzed, by immunohistochemistry along with microwave antigen retrieval, the expression of pS2 protein in a retrospective series of 236 human primary neuro-endocrine tumours and attempted to correlate this with the clinicopathologic features of patients and the presence of oestrogen receptor (ER). pS2 immunoreactivity was detected in 42% of small-cell lung carcinomas, 36% of lung carcinoids, 33% of phaeochromocytomas, 38% of carotid-body tumours, 31% of pancreatic neuro-endocrine tumours, 60% of stomach carcinoids, 55% of ileal carcinoids, 23% of appendiceal carcinoids and 86% of rectal carcinoids respectively in more than 10% tumour cells. No pituitary tumours displayed pS2 immunoreactivity. pS2 transcript was also detected in lung carcinoid and carotid-body tumours by Northern-blot analysis. There was a statistically higher incidence of pS2 expression in carcinoid tumours of the ileum and rectum than in those of the appendix. No association was observed between pS2 expression and the occurrence of the carcinoid syndrome; nor was any correlation observed between the occurrence of pS2 immunoreactivity and that of ER. Our results suggest that the expression of the pS2 protein in a wide spectrum of neuro-endocrine tumours may be implicated in the pathogenesis and progression of some neuro-endocrine tumours in an oestrogen-independent pathway.
PMID: 9221803 [PubMed - indexed for MEDLINE]
1: Gut. 2003 Sep;52(9):1308-16.
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Comment in:
• Gut. 2003 Sep;52(9):1237-9.
Autocrine growth inhibition by transforming growth factor beta-1 (TGFbeta-1) in human neuroendocrine tumour cells.
Wimmel A, Wiedenmann B, Rosewicz S.
Medizinische Klinik mit Schwerpunkt Hepatologie, Gastroenterologie, Endokrinologie und Stoffwechsel, CVK, Charite, Augustenburger Platz 1, D-13353, Berlin, Germany.
BACKGROUND AND AIM: The role of transforming growth factor beta-1 (TGFbeta-1) in neuroendocrine tumour biology is currently unknown. We therefore examined the expression and biological significance of TGFbeta signalling components in neuroendocrine tumours (NETs) of the gastroenteropancreatic (GEP) tract. METHODS: Expression of TGFbeta-1 and its receptors, Smads and Smad regulated proteins, was examined in surgically resected NET specimens and human NET cell lines by immunohistochemistry, reverse transcriptase-polymerase chain reaction, immunoblotting, and ELISA. Activation of TGFbeta-1 dependent promoters was tested by transactivation assays. Growth regulation was evaluated by cell numbers, soft agar assays, and cell cycle analysis using flow cytometry. The role of endogenous TGFbeta was assessed by a TGFbeta neutralising antibody and stable transfection of a dominant negative TGFbetaR II receptor construct. RESULTS: Coexpression of TGFbeta-1 and its receptors TGFbetaR I and TGFbetaR II was detected in 67% of human NETs and in all three NET cell lines examined. NET cell lines expressed the TGFbeta signal transducers Smad 2, 3, and 4. In two of the three cell lines, TGFbeta-1 treatment resulted in transactivation of a TGFbeta responsive reporter construct as well as inhibition of c-myc and induction of p21((WAF1)) expression. TGFbeta-1 inhibited anchorage dependent and independent growth in a time and dose dependent manner in TGFbeta-1 responsive cell lines. TGFbeta-1 mediated growth inhibition was due to G1 arrest without evidence of induction of apoptosis. Functional inactivation of endogenous TGFbeta revealed the existence of an autocrine antiproliferative loop in NET cells. CONCLUSIONS: Neuroendocrine tumour cells of the gastroenteropancreatic tract are subject to paracrine and autocrine growth inhibition by TGFbeta-1, which may account in part for the low proliferative index of this tumour entity.
PMID: 12912863 [PubMed - indexed for MEDLINE]
1: J Pathol. 1999 May;188(1):51-5.
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Comment in:
• J Pathol. 1999 Dec;189(4):627-8.
Prognostic value of p53, bcl-2, and c-erbB-2 protein expression in phaeochromocytomas.
de Krijger RR, van der Harst E, van der Ham F, Stijnen T, Dinjens WN, Koper JW, Bruining HA, Lamberts SW, Bosman FT.
Department of Pathology, Erasmus University and University Hospital, Rotterdam, The Netherlands.
dekrijger@path.fgg.eur.nl
Many studies have tried to discriminate malignant from benign phaeochromocytomas, but until now no widely accepted histological, immunohistochemical, or molecular methods have been available. In this study of 29 malignant and 85 benign phaeochromocytomas from 102 patients, immunohistochemistry was performed with antibodies to the tumour suppressor gene product p53 and the proto-oncogene products bcl-2 and c-erbB-2, using the avidin-biotin complex method. Malignant phaeochromocytomas showed a statistically significant higher frequency of p53 (p=0.042) and bcl-2 (p=0.037) protein expression than their benign counterparts. The combination of both markers showed an even higher significance (p=0.004), to which both markers contributed equally. Overexpression of c-erbB-2 was associated with the occurrence of familial phaeochromocytomas (p=0. 001), but no difference was found between benign and malignant cases. In conclusion, p53, bcl-2, and c-erbB-2 all appear to be involved in the pathogenesis of a proportion of phaeochromocytomas. Immunoreactivity to p53 and bcl-2 proteins may help to predict the clinical behaviour of phaeochromocytomas. Copyright 1999 John Wiley & Sons, Ltd.
PMID: 10398140 [PubMed - indexed for MEDLINE]
1: Virchows Arch. 1995;426(4):361-7.
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Immunohistochemical distribution of chromogranins A and B and secretogranin II in neuroendocrine tumours of the gastrointestinal tract.
Fahrenkamp AG, Wibbeke C, Winde G, Ofner D, Bocker W, Fischer-Colbrie R, Schmid KW.
Department of Pathology, University of Munster, Germany.
The aim of the present study was to investigate immunohistochemically the distribution of chromogranin A, chromogranin B, and secretogranin II in a series of 152 neuroendocrine tumours of the gastrointestinal tract. Tumour tissues from 25 argyrophil gastric carcinoids, 18 gastrin and 5 somatostatin-producing tumours, 4 'gangliocytic paragangliomas', 49 classical argentaffin and 2 L cell appendiceal carcinoids, 27 classical ileal carcinoids, 17 rectal carcinoids, and 5 poorly differentiated neuroendocrine tumours of the stomach and rectum were immunostained with antibodies against chromogranin A, chromogranin B, and secretogranin II. Chromogranin A was the major granin expressed in gastric carcinoids and in serotonin-producing carcinoids of the appendix and the ileum. In contrast, strong chromogranin B and secretogranin II immunoreactivity was found in rectal carcinoids, in which chromogranin A was rarely expressed. Since chromogranin A is a widely used marker for neuroendocrine differentiation, it is of diagnostic importance that some gastrin-producing tumours, 'gangliocytic paragangliomas', poorly differentiated neuroendocrine carcinomas, and appendiceal L cell carcinoids completely lacked chromogranin A positivity. It is concluded that the various neuroendocrine tumours of the gastrointestinal tract show distinctly different patterns of granin expression, probably reflecting their histogenetical origin.
PMID: 7599788 [PubMed - indexed for MEDLINE]
1: Neuroendocrinology. 2004;80 Suppl 1:8-11.
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Tumour biology of gastroenteropancreatic neuroendocrine tumours.
Grotzinger C.
Department of Internal Medicine, Division of Hepatology and Gastroenterology, Charite, Campus Virchow Hospital, University Medicine Berlin, Berlin, Germany.
carsten.groetzinger@charite.de
Neuroendocrine tumours of the gastroenteropancreatic tract (GEP NETs) represent a rare and heterogeneous group of tumours. Based on their ontogenetic origin, GEP NETs are classified into foregut, midgut and hindgut tumours. Although they have many features in common, their molecular backgrounds are obviously different. Elucidation of the key factors determining tumour biology has been hampered by the low incidence and high variability of these tumours in terms of origin, morphology and growth. However, recent years have shed some light on molecular genetics of these tumours, revealing important genetic factors as the RET proto-oncogene and the tumour suppressor menin as well as knowledge about the role of growth factors like IGF-1, TGF-beta, VEGF and PDGF for the regulation of differentiation, growth and secretion. In the future, emerging molecular tools in rapid individual genome analysis and in proteomic and array technologies may help to delineate common patterns of NET disease.
Publication Types:
• Review
PMID: 15477708 [PubMed - indexed for MEDLINE]
1: Ann N Y Acad Sci. 1994 Sep 15;733:46-55.
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Expression of growth factors and their receptors in neuroendocrine gut and pancreatic tumors, and prognostic factors for survival.
Oberg K.
Department of Internal Medicine, University Hospital, Uppsala, Sweden.
Publication Types:
• Review
PMID: 7978895 [PubMed - indexed for MED
strointest Surg. 2006 Mar;10(3):327-31.
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Surgery for primary pancreatic neuroendocrine tumors.
Norton JA.
Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California, USA.
janorton@stanford.edu
PMID: 16504877 [PubMed - in process]