Title: Promoting role of cholecystokinin 2 receptor (CCK2R) in gastrointestinal stromal tumours pathogenesis
Authors: Quattrone, Anna
Dewaele, Barbara
Wozniak, Agnieszka
Bauters, Marijke
Vanspauwen, Vanessa
Floris, Guiseppe
Schöffski, Patrick
Chibon, Frederic
Coindre, Jean-Michel
Sciot, Raf
Debiec-Rychter, Maria # ×
Issue Date: Jul-2012
Publisher: Longman
Series Title: Journal of Pathology vol:228 issue:4 pages:565-574
Abstract: The cholecystokinin 2 receptor (CCK2R/CCKBR) is expressed in gastrointestinal stromal tumours (GIST). We sought to investigate the role of CCK2R in GIST pathogenesis. Molecular characterization of CCK2R was performed on a heterogeneous cohort of 50 GIST. In addition, CCK2R expression was evaluated by immunohistochemistry (IHC) using tissue microarray (TMA) containing 292 GIST, two cases of hyperplasia of interstitial Cajal's cells (ICC) and six gastric microscopic GIST. Mono-allelic loss of the CCK2R/11p15 allele was identified in 13.7% of GIST, having no impact on the level of CCK2R transcript expression. No CCK2R mutations were found. The CCK2Ri4sv, CCK2R splice variant with retention of intron 4, was detected in 6 out of 20 analysed tumours. Wild-type CCK2R transcripts were commonly expressed (57.1% of cases) and this expression highly correlated with gastric primary site of GIST (p<0.001). On protein level, expression of CCK2R in incidental ICC hyperplasia and early stages of gastric GIST development was documented, and its gastric association was confirmed on GIST-TMA by IHC. To explore the in vivo effect of CCK2R activation on tumour growth, gastrin versus placebo was administered intra-peritoneally in nude mice carrying human GIST xenografts. The tumour volume was followed up for ten weeks. The effect of this stimulation on tumour cell proliferation/apoptosis was assessed by IHC, and KIT/PKC-theta signalling was evaluated by Western blotting (WB). In vivo experiments showed a two-fold increase in the volume of tumours which were exposed to gastrin in comparison with non-exposed controls (p = 0.03), with a significant increase in mitotic activity (p= 0.04) and Ki-67 proliferation index (p = 0.008). By WB, gastrin stimulation resulted in hyper-activation of KIT and PKC-theta kinases, and in evident PI3K/AKT pathway over-activation. Our results indicate a promoting role of CCK2R on GIST tumourigenesis, particularly in tumours of gastric origin. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
ISSN: 0022-3417
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Human Genome Laboratory
Translational Cell & Tissue Research
Laboratory for Genetics of Malignant Disorders
Laboratory of Experimental Oncology
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Quattrone.pdfpublisher's version pdf Published 662KbAdobe PDFView/Open


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science