Systematic Reviews
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2016; 22(12): 3471-3485
Published online Mar 28, 2016. doi: 10.3748/wjg.v22.i12.3471
Glucose metabolic phenotype of pancreatic cancer
Anthony KC Chan, Jason IE Bruce, Ajith K Siriwardena
Anthony KC Chan, Ajith K Siriwardena, Regional Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Manchester M13 9WL, United Kingdom
Jason IE Bruce, Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, United Kingdom
Author contributions: Chan AKC, Bruce JIE and Siriwardena AK conceptualised and designed the review; Chan AKC performed the systematic review; Chan AKC and Siriwardena A analysed the data; Chan AKC drafted the initial manuscript; all authors reviewed and approved the final manuscript as submitted.
Conflict-of-interest statement: No authors have any commercial interests in this work.
Data sharing statement: Detailed systematic review dataset available from the corresponding author at ajith.siriwardena@cmft.nhs.uk.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ajith K Siriwardena, MD, FRCS, Professor, Hepato-Pancreato-Biliary Surgery Unit, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, United Kingdom. ajith.siriwardena@cmft.nhs.uk
Telephone: +44-161-2764250 Fax: +44-161-2764530
Received: December 18, 2015
Peer-review started: December 22, 2015
First decision: January 13, 2016
Revised: January 30, 2016
Accepted: March 1, 2016
Article in press: March 2, 2016
Published online: March 28, 2016
Abstract

AIM: To construct a global “metabolic phenotype” of pancreatic ductal adenocarcinoma (PDAC) reflecting tumour-related metabolic enzyme expression.

METHODS: A systematic review of the literature was performed using OvidSP and PubMed databases using keywords “pancreatic cancer” and individual glycolytic and mitochondrial oxidative phosphorylation (MOP) enzymes. Both human and animal studies investigating the oncological effect of enzyme expression changes and inhibitors in both an in vitro and in vivo setting were included in the review. Data reporting changes in enzyme expression and the effects on PDAC cells, such as survival and metastatic potential, were extracted to construct a metabolic phenotype.

RESULTS: Seven hundred and ten papers were initially retrieved, and were screened to meet the review inclusion criteria. 107 unique articles were identified as reporting data involving glycolytic enzymes, and 28 articles involving MOP enzymes in PDAC. Data extraction followed a pre-defined protocol. There is consistent over-expression of glycolytic enzymes and lactate dehydrogenase in keeping with the Warburg effect to facilitate rapid adenosine-triphosphate production from glycolysis. Certain isoforms of these enzymes were over-expressed specifically in PDAC. Altering expression levels of HK, PGI, FBA, enolase, PK-M2 and LDA-A with metabolic inhibitors have shown a favourable effect on PDAC, thus identifying these as potential therapeutic targets. However, the Warburg effect on MOP enzymes is less clear, with different expression levels at different points in the Krebs cycle resulting in a fundamental change of metabolite levels, suggesting that other essential anabolic pathways are being stimulated.

CONCLUSION: Further characterisation of the PDAC metabolic phenotype is necessary as currently there are few clinical studies and no successful clinical trials targeting metabolic enzymes.

Keywords: Metabolism, Pancreatic cancer, Warburg effect, Metabolic inhibitor, Glycolysis, Krebs cycle

Core tip: Our systematic review constructs a global “metabolic phenotype” of pancreatic ductal adenocarcinoma (PDAC) reflecting tumour-related metabolic enzyme expression. We show that the Warburg effect is consistently demonstrated, with the over-expression of glycolytic enzymes and lacate dehydrogenase to facilitate rapid adenosine-triphosphate (ATP) production from glycolysis. We also show that the Warburg effect on mitochrondial oxidative phosphorylation in PDAC is more varied and not solely focused on ATP production, but also to stimulate other anabolic pathways for the purposes of tumourigencity. The metabolic phenotype provides an overview essential to elucidating the pathological changes that occur in PDAC.