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Ghrelin and Gastrin in Advanced Gastric Cancer Before and After Gastrectomy

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Ghrelin and Gastrin in Advanced Gastric Cancer Before and After Gastrectomy Online Submissions: http://www.wjgnet.com/1007-9327office World J Gastroenterol 2011 January 28; 17(4): 449-458 [email protected] ISSN 1007-9327 (print) ISSN 2219-2840 (online) doi:10.3748/wjg.v17.i4.449 © 2011 Baishideng. All rights reserved. ORIGINAL ARTICLE Ghrelin and gastrin in advanced gastric cancer before and after gastrectomy Anna Zub-Pokrowiecka, Kazimierz Rembiasz, Peter C Konturek, Andrzej Budzyński, Stanisław J Konturek, Marek Winiarski, Władysław Bielański Anna Zub-Pokrowiecka, Kazimierz Rembiasz, Peter C Kontu- 10 patients with GC 4-5 years after (total or subtotal) rek, Andrzej Budzyński, Stanisław J Konturek, Marek Winiar- gastrectomy; (3) 25 healthy H. pylori-negative controls, ski, Władysław Bielański, Department of Physiology, Medical matched by age and BMI to the above two groups; College, Jagiellonian University, 31-531, Cracow, Poland and (4) 10 GC patients 4-5 years after total gastrec- Anna Zub-Pokrowiecka, Kazimierz Rembiasz, Peter C Kontu- tomy. Ghrelin and gastrin plasma concentrations were rek, Andrzej Budzyński, Stanisław J Konturek, Marek Winiar- measured by specific radioimmunoassay under fasting ski, Władysław Bielański, 2nd Department of General Surgery, conditions and postprandially at 60 and 90 min after in- Medical College, Jagiellonian University, 31-531, Cracow, Poland Anna Zub-Pokrowiecka, Kazimierz Rembiasz, Peter C Kontu- gestion of a mixed meal. GHS-R expression was exam- rek, Andrzej Budzyński, Stanisław J Konturek, Marek Winiar- ined in biopsy samples from intact healthy mucosa and ski, Władysław Bielański, Department of Medicine, Thuringia GC tissue using semi-quantitative reverse transcription- Clinic Georgius Agricola Saalfeld Teaching Hospital University polymerase chain reaction. Jena, 07318, Saalfeld, Germany Author contributions: Zub-Pokrowiecka A, Rembiarz K, Win- RESULTS: In healthy controls, fasting plasma ghrelin iarski M and Budzyński A interviewed and examined patients; levels were significantly elevated and declined marked- Konturek PC and Bielański W performed reverse transcption- ly at 60 and 90 min after a mixed meal. The concomi- polymerase chain reaction and radioimmunoassays; Konturek SJ tant enhanced ghrelin, GHS-R and gastrin expression in designed the study and drafted the manuscript; all authors read GC tissue over that recorded in intact mucosa, and the and approved the final manuscript. marked rise in plasma gastrin in these subjects under Supported by The Ministry of Science and Higher Education in fasting conditions indicate the role of these hormonal Poland Grant K/PBP/000012 for 2006-2008 and by Jagiellonian University Medical College Research Project for 2006-2009 factors in GC formation. Fasting plasma levels and Correspondence to: Stanislaw J Konturek, Professor MD, postprandial response of ghrelin and gastrin appear Department of Physiology, Medical College, Jagiellonian Uni- to be inversely correlated in healthy subjects. Feeding versity, Grzegorzecka 16, 31-531, Cracow, in the controls resulted in a significant fall in plasma Poland. [email protected] ghrelin with a subsequent rise in plasma gastrin, but Telephone: +48-12-605604 Fax: +48-12-211578 in H. pylori -positive GC patients submitted to total or Received: June 4, 2010 Revised: August 6, 2010 distal gastrectomy, feeding failed to affect significantly Accepted: September 13, 2010 the fall in plasma ghrelin that was recorded in these Published online: January 28, 2011 patients before surgery. Fasting ghrelin concentrations were significantly lower in patients 4-5 years after total gastrectomy compared to those in healthy controls and to these in GC patients before surgery. Abstract AIM: To investigate plasma ghrelin, gastrin and growth CONCLUSION: Elevated plasma gastrin and suppres- hormone secretagogue receptor (GHS-R) expression in sion of fasting ghrelin in patients with GC suggest the advanced gastric cancer (GC) before and after resection. existence of a close relationship between these two hor- mones in gastric carcinogenesis. METHODS: Seventy subjects in whom endoscopy of the upper gastrointestinal tract was performed in the © 2011 Baishideng. All rights reserved. Department of General Surgery at Cracow University during the past decade: (1) 25 patients with GC associ- Key words: Ghrelin; Gastrin; Gastric cancer; Gastric ated with Helicobacter pylori (H. pylori ) infection; (2) resection WJG|www.wjgnet.com 449 January 28, 2011|Volume 17|Issue 4| Zub-Pokrowiecka A et al . Ghrelin/gastrin in gastric cancer Peer reviewer: Guida Portela-Gomes, Professor of University A CCK of Lisbon, Department of Medicine, Rua Domingos Sequei- ECL cell ra-128, Estoril, 2765-525, Portugal 2 Histamine Gastrin Zub-Pokrowiecka A, Rembiasz K, Konturek PC, Budzyński A, Ri H2 Konturek SJ, Winiarski M, Bielański W. Ghrelin and gastrin in ACh A CCK M3 Gs Gi advanced gastric cancer before and after gastrectomy. World J C 2 Gastroenterol 2011; 17(4): 449-458 Available from: URL: http:// Ca++ ATP cAMP Ca++ www.wjgnet.com/1007-9327/full/v17/i4/449.htm DOI: http:// K+ dx.doi.org/10.3748/wjg.v17.i4.449 PAR/ETAL cell H+K+ ATPase H+ INTRODUCTION B Fundus Ghrelin, a natural ligand for growth hormone secreta- Esophagus gogue receptor (GHS-R), was originally identified in rat Cardia Gr gastric mucosa and shown to be expressed by the endo- cell Parietal [1,2] Ghrelin cell crine ghrelin (Gr)-cells of this mucosa . These Gr-cells, SST represent about 20% of the total population of endocrine Angularis Curve cell Histamine incisura cells in human gastric mucosa, and are located in the lower Lesser ECL parts of the oxyntic glands in the fundus and body of the Antrum cell + G stomach. Gastric acid secretion is stimulated physiologi- Body (corpus) cell [2-6] SST cally by gastrin and histamine as well as by ghrelin itself Stimulation Gastrin cell (Figure 1). Antrum Inhibition Duodenum Ghrelin is a stimulant of GH secretion, which acts via release of GHS-R in the stomach, but characteristically, it Figure 1 Gastric secretory mechanism at the parietal cell (oxyntic) level (A) is also the only circulatory gastrointestinal hormone that and at the level of the whole stomach (B). is known to be secreted by the empty (fasting) stomach, to enhance food intake and maintain energy homeostasis fol- [6] centrations in patients at 4-5 years after total and distal lowing its central or peripheral administration . Ghrelin gastrectomy was assessed to elucidate the possible com- is currently considered as the most powerful endogenous pensatory extragastric production of these hormones. orexigenic (appetite-stimulating) hormone, which results in a positive energy balance[4,6,7]. Its action on gastric mu- cosa might contribute to carcinogenesis, but the role of MATERIALS AND METHODS ghrelin/GHS-R in gastric cancer (GC) pathogenesis[8] awaits explanation, and possible use of ghrelin in severe The study included 70 patients, aged 18 and over who, gastric-originated cachexia remains unknown. from January 2006 to May 2008, underwent upper gas- The reduction in the ghrelin levels after gastrectomy by trointestinal tract endoscopy in a specialized unit of the > 60% supports the notion that the gastric mucosa is the Department of Surgery, Jagiellonian University Medical main site of ghrelin production[3,4,9]. Gastric cancer modi- College, Cracow. fies the expression of ghrelin in gastric mucosa and this Exclusion criteria included any of the following: age < could be attributed, at least in part, to severe atrophic gas- 18 years; no consent to participate in the study; a history tritis[10,11], which usually precedes and might lead to gastric of diabetes, thyroid disease and neuroendocrine tumors, carcinogenesis. Mottershead et al[12] have observed a lack of use of glucocorticoids, progesterone or testosterone, renal expression of mRNA for ghrelin in GC cells by immuno- and/or liver failure; prior chemotherapy (not applicable histochemical and reverse transcription-polymerase chain to a group of patients 4-5 years after gastrectomy); drugs and/or alcohol addiction; and body mass index (BMI) reaction methods. According to our recent experience, the 2 expression of mRNA for ghrelin in pronounced atrophic > 30 kg/m . Patients included in the research program gastritis is relatively low, so major changes in plasma ghre- based on the above criteria were assigned to one of the lin cannot originate from the Helicobacter pylori (H. pylori)- following groups: (1) 25 patients with GC associated with related atrophic gastritis tissue[12]. H. pylori infection; (2) 10 patients with GC 4-5 years after The aim of the present study was to analyze the (total or subtotal) gastrectomy; (3) 25 healthy H. pylori- plasma concentrations of the ghrelin-GHS-R complex in negative controls, matched by age and BMI to the above patients with advanced GC before and after total or dis- two groups; and (4) 10 GC patients 4-5 years after total tal gastrectomy. In addition, we analyzed plasma ghrelin gastrectomy. The basis of this categorization was the ini- concentrations and mucosal gene expression of ghrelin tial diagnosis upon admission to our gastrointestinal unit and its receptor, GHR-S, in intact mucosa and in H. pylori- (Table 1). The study was approved and supervised by the infected GC tissue. Moreover, the analysis of fasting and Institutional Research Ethical Committee and informed postprandial plasma ghrelin levels vs plasma gastrin con- consent was obtained from each participant in this study. WJG|www.wjgnet.com 450 January 28, 2011|Volume 17|Issue 4| Zub-Pokrowiecka
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