Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine TumorsSummary
Background & Aims: In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR...
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Elsevier
2020-01-01
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Series: | Cellular and Molecular Gastroenterology and Hepatology |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X20300175 |
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doaj-fa9e77fa8ab04349aa617d5d954be8d7 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Katie A. Lloyd Bryony N. Parsons Michael D. Burkitt Andrew R. Moore Stamatia Papoutsopoulou Malcolm Boyce Carrie A. Duckworth Klaire Exarchou Nathan Howes Lucille Rainbow Yongxiang Fang Claus Oxvig Steven Dodd Andrea Varro Neil Hall D. Mark Pritchard |
spellingShingle |
Katie A. Lloyd Bryony N. Parsons Michael D. Burkitt Andrew R. Moore Stamatia Papoutsopoulou Malcolm Boyce Carrie A. Duckworth Klaire Exarchou Nathan Howes Lucille Rainbow Yongxiang Fang Claus Oxvig Steven Dodd Andrea Varro Neil Hall D. Mark Pritchard Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine TumorsSummary Cellular and Molecular Gastroenterology and Hepatology Tumorigenesis Carcinogenesis Mouse Model Hormone Signal Transduction |
author_facet |
Katie A. Lloyd Bryony N. Parsons Michael D. Burkitt Andrew R. Moore Stamatia Papoutsopoulou Malcolm Boyce Carrie A. Duckworth Klaire Exarchou Nathan Howes Lucille Rainbow Yongxiang Fang Claus Oxvig Steven Dodd Andrea Varro Neil Hall D. Mark Pritchard |
author_sort |
Katie A. Lloyd |
title |
Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine TumorsSummary |
title_short |
Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine TumorsSummary |
title_full |
Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine TumorsSummary |
title_fullStr |
Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine TumorsSummary |
title_full_unstemmed |
Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine TumorsSummary |
title_sort |
netazepide inhibits expression of pappalysin 2 in type 1 gastric neuroendocrine tumorssummary |
publisher |
Elsevier |
series |
Cellular and Molecular Gastroenterology and Hepatology |
issn |
2352-345X |
publishDate |
2020-01-01 |
description |
Background & Aims: In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling. Methods: We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGSGR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. Results: Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGSGR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGSGR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. Conclusions: In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide. |
topic |
Tumorigenesis Carcinogenesis Mouse Model Hormone Signal Transduction |
url |
http://www.sciencedirect.com/science/article/pii/S2352345X20300175 |
work_keys_str_mv |
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doaj-fa9e77fa8ab04349aa617d5d954be8d72020-11-25T03:17:07ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2020-01-01101113132Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine TumorsSummaryKatie A. Lloyd0Bryony N. Parsons1Michael D. Burkitt2Andrew R. Moore3Stamatia Papoutsopoulou4Malcolm Boyce5Carrie A. Duckworth6Klaire Exarchou7Nathan Howes8Lucille Rainbow9Yongxiang Fang10Claus Oxvig11Steven Dodd12Andrea Varro13Neil Hall14D. Mark Pritchard15Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United KingdomDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomTrio Medicines, Ltd, Hammersmith Medicines Research, London, United KingdomDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United KingdomLiverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United KingdomCentre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United KingdomCentre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United KingdomDepartment of Molecular Biology and Genetics, Aarhus University, Aarhus C, DenmarkDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United KingdomCentre for Genomic Research, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; The Earlham Institute, Norwich, Norfolk, United Kingdom; School of Biological Sciences, University of East Anglia, Norwich, Norfolk, United KingdomDepartment of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Liverpool University Hospitals, National Health Service Foundation Trust, Liverpool, United Kingdom; Correspondence Address correspondence to: D. Mark Pritchard, PhD, FRCP, Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, The Henry Wellcome Laboratory, Nuffield Building, Crown Street, Liverpool L69 3GE, United Kingdom. fax: 0151 794 6825.Background & Aims: In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling. Methods: We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGSGR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. Results: Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGSGR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGSGR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. Conclusions: In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide.http://www.sciencedirect.com/science/article/pii/S2352345X20300175TumorigenesisCarcinogenesisMouse ModelHormoneSignal Transduction |