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Characterization of Endocrine Cells and Tumours in the Stomach
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Enterochromaffin-like (ECL) and ghrelin cells, in the human gastric mucosa and in gastric endocrine tumours (GETs), were subclassified with respect to immunohistochemical reaction vs. vesicular monoamine transporter 2 (VMAT-2), ghrelin/obestatin, and histidine decarboxylase (HDC). The immunohistochemical expression of ghrelin/obestatin and HDC in GETs was related/correlated to plasma ghrelin/obestatin and urinary methyl imidazole acetic acid (U-MeImAA) excretion respectively, with the intention of identifying markers for these tumour types.

ECL cells in the gastric mucosa appear either with VMAT-2 only, or with HDC immunoreactivity only, or they can express both proteins; but in GETs the transporter protein and the enzyme were almost always co-expressed in the same cells. Furthermore, ghrelin and obestatin were co-localized in the same cells in the gastric mucosa and in the tumours. In the gastric mucosa, occasional ghrelin/obestatin cells expressed VMAT-2, but in GETs these proteins were always co-localized. Ghrelin expressing cells were non-immunoreactive to HDC. Plasma ghrelin/obestatin concentrations remained low in patients with GETs, irrespective of the relative incidence of these cells in the mucosa and in tumours. The plasma values were not related/correlated to various clinico-pathological parameters. A malignant ghrelinoma was however an exception. The tumour released high total and active ghrelin concentrations into the blood circulation. The patient suffered from diarrhoea, hypothyroidism and diabetes mellitus, but it is not clear if these conditions were due to hyperghrelinaemia. The excretion U-MeImAA was increased in a few patients with GETs, but this increase was not always related to clinical symptoms.

In conclusion, ECL cells are an heterogeneous group according to VMAT-2 and HDC immunoreactivity. Ghrelin and obestatin are expressed in the same cells in the gastric mucosa, and a few of these cells display VMAT-2 immunoreactivity. Ghrelinoma is a new gastric tumour entity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2008. , p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 356
Keywords [en]
Oncology, ECL cells, ghrelin cells, gastric endocrine tumours, VMAT-2, ghrelin, obestatin, HDC, U-MeImAA
Keywords [sv]
Onkologi
Identifiers
URN: urn:nbn:se:uu:diva-8804ISBN: 978-91-554-7208-5 (print)OAI: oai:DiVA.org:uu-8804DiVA, id: diva2:172096
Public defence
2008-05-28, Enghoffsalen, Entrance 50, University Hospital, Uppsala, 09:15
Opponent
Supervisors
Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2010-12-20Bibliographically approved
List of papers
1. Ghrelin Immunoreactive Cells in Gastric Endocrine Tumors and Their Relation to Plasma Ghrelin Concentration: Ghrelin in Gastric Endocrine Tumors
Open this publication in new window or tab >>Ghrelin Immunoreactive Cells in Gastric Endocrine Tumors and Their Relation to Plasma Ghrelin Concentration: Ghrelin in Gastric Endocrine Tumors
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2008 (English)In: Journal of Clinical Gastroenterology, ISSN 0192-0790, E-ISSN 1539-2031, Vol. 42, no 4, p. 381-388Article in journal (Refereed) Published
Abstract [en]

GOALS: Our aim was to elucidate the incidence and distribution pattern of ghrelin-immunoreactive (IR) cells in various types of human gastric endocrine tumors, and their surrounding mucosa, and relate the findings to total ghrelin concentrations in plasma. BACKGROUND: It has been demonstrated previously, that ghrelin-IR cells are present not only in normal human gastric oxyntic mucosa, but also in all types of enterochromaffinlike (ECL) cell carcinoids (ECL-CCs), and in mucosal regions affected by ECL cell hyperplasia. STUDY: Forty-eight gastric endocrine tumors were included in the study: 32 type I ECL-CCs, 3 type II, 9 type III, 1 non-ECL-CC, and 3 poorly differentiated endocrine carcinomas. The tumors were analyzed immunohistochemically with antibodies raised versus chromogranin A, synaptophysin, serotonin, somatostatin, vesicular monoamine transporter 2 and ghrelin. Total ghrelin in plasma was measured in 20 patients, using a commercial radioimmunoassay kit. RESULTS: Ghrelin-IR cells were found in all types I and II ECL-CCs but in only a few cases of the other tumors. Ghrelin-IR cells were also found among the hyperplastic endocrine cells in the mucosa surrounding types I and II, where they showed diffuse, linear, nodular and adenomatoid hyperplasia patterns. In type III ECL-CCs and poorly differentiated endocrine carcinomas, only diffuse and linear ghrelin-IR cell hyperplasia was present in the oxyntic mucosa in about half of the cases, whereas the mucosa of the non-ECL-CC did not show this feature. CONCLUSIONS: Despite the frequent occurrence of ghrelin-IR cells in both the neoplastic parenchyma and the oxyntic mucosa, plasma total ghrelin concentrations remained within the reference range and can therefore not be used as a clinical marker to identify ghrelin expressing ECL-CCs or ghrelin cell hyperplasia.

Keywords
ECL cells, gastric endocrine tumor, ghrelin, immunohistochemistry, radioimmunoassay
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97241 (URN)10.1097/MCG.0b013e318032338c (DOI)000254629300011 ()18277901 (PubMedID)
Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2017-12-14Bibliographically approved
2. Malignant Gastric Ghrelinoma with Hyperghrelinemia: Malignant Gastric Ghrelinoma
Open this publication in new window or tab >>Malignant Gastric Ghrelinoma with Hyperghrelinemia: Malignant Gastric Ghrelinoma
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2004 (English)In: The Journal of Clinical Endocrinology & Metabolism, ISSN 0021-972, Vol. 89, no 8, p. 3739-3744Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97242 (URN)
Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2010-05-05Bibliographically approved
3. Obestatin/ghrelin cells in normal mucosa and endocrine tumours of the stomach
Open this publication in new window or tab >>Obestatin/ghrelin cells in normal mucosa and endocrine tumours of the stomach
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2009 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 160, no 6, p. 941-949Article in journal (Refereed) Published
Abstract [en]

Objective:

Obestatin and ghrelin are derived from the same gene and co-expressed in the same endocrine cells. Vesicular monoamine transporter-2 (VMAT-2), a marker for enterochromaffin-like (ECL) cells, is considered to be expressed in ghrelin cells. The aim was to establish if the two peptides and the transporter are co-expressed, both in normal gastric mucosa and in gastric endocrine tumours.

Design:

An immunohistochemical study was performed on gastric biopsy material and on surgical specimens from 63 patients with gastric endocrine tumours and from individuals with normal gastric mucosa. Cells displaying obestatin immunoreactivity were examined regarding co-localization with ghrelin and VMAT-2. Both single- and double-immunostaining techniques were applied. Obestatin concentration in blood was measured in a subgroup of these patients. The results were correlated to various clinico-pathological parameters.

Results:

In the normal mucosa, obestatin/ghrelin-immunoreactive cells rarely co-expressed VMAT-2. In most tumour tissue specimens, only a fraction of neoplastic cells displayed immunoreactivity to obestatin, and these cells always co-expressed ghrelin. Neoplastic obestatin-/ ghrelin-IR cells invariably expressed VMAT-2, except for two ghrelinomas. The obestatin concentrations in blood were consistently low and did not correlate to clinico-pathological data.

Conclusions:

Obestatin and ghrelin immunoreactivity always occurred in the same endocrine cells in the gastric mucosa but these cells only occasionally co-expressed VMAT-2, opposite to the findings in tumours. These results indicate that endocrine cells expressing obestatin and ghrelin mainly differ from VMAT-2 expressing cells (ECL-cells) and can develop into pure ghrelinomas. Plasma concentrations of obestatin did not correlate to cellular expression.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97243 (URN)10.1530/EJE-09-0001 (DOI)000272934600008 ()19289536 (PubMedID)
Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2017-12-14Bibliographically approved
4. Expression of histidine decarboxylase and vesicular monoamine transporter 2 in human enterochromaffin-like cells and gastric endocrine tumours: HDC and VMAT-2 in ECL cells
Open this publication in new window or tab >>Expression of histidine decarboxylase and vesicular monoamine transporter 2 in human enterochromaffin-like cells and gastric endocrine tumours: HDC and VMAT-2 in ECL cells
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-97244 (URN)
Available from: 2008-05-06 Created: 2008-05-06 Last updated: 2010-01-13Bibliographically approved

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