Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. May 15, 2021; 13(5): 312-331
Published online May 15, 2021. doi: 10.4251/wjgo.v13.i5.312
Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers
Ross King, Conall Hayes, Claire L Donohoe, Margaret R Dunne, Maria Davern, Noel E Donlon
Ross King, Conall Hayes, Claire L Donohoe, Margaret R Dunne, Maria Davern, Noel E Donlon, Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
Author contributions: King R wrote the manuscript; King R, Hayes C, Donohoe CL, Dunne MR, Davern M and Donlon NE conceived the work and made substantial revisions to and critique of the content; Davern M and Donlon NE contributed equally to this manuscript; all authors have read and approved the final manuscript.
Conflict-of-interest statement: The authors report no known conflict of interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (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:
Corresponding author: Noel E Donlon, BM BCh, Surgical Oncologist, Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, James Street, Dublin D8, Ireland.
Received: December 27, 2020
Peer-review started: December 27, 2020
First decision: February 14, 2021
Revised: February 24, 2021
Accepted: April 14, 2021
Article in press: April 14, 2021
Published online: May 15, 2021

The malfeasant role of the hypoxic tumour microenvironment (TME) in cancer progression was recognized decades ago but the exact mechanisms that augment the hallmarks of cancer and promote treatment resistance continue to be elucidated. Gastroesophageal cancers (GOCs) represent a major burden of worldwide disease, responsible for the deaths of over 1 million people annually. Disentangling the impact of hypoxia in GOCs enables a better overall understanding of the disease pathogenesis while shining a light on novel therapeutic strategies and facilitating precision treatment approaches with the ultimate goal of improving outcomes for patients with these diseases. This review discusses the underlying principles and processes of the hypoxic response and the effect of hypoxia in promoting the hallmarks of cancer in the context of GOCs. We focus on its bidirectional influence on inflammation and how it drives angiogenesis, innate and adaptive immune evasion, metastasis, and the reprogramming of cellular bioenergetics. The contribution of the hypoxic GOC TME to treatment resistance is examined and a brief overview of the pharmacodynamics of hypoxia-targeted therapeutics is given. The principal methods that are used in measuring hypoxia and how they may enhance prognostication or provide rationale for individually tailored management in the case of tumours with significant hypoxic regions are also discussed.

Keywords: Esophageal cancer, Gastric cancer, Tumor hypoxia, Tumour microenvironment, Gastroesophageal cancer

Core Tip: Improved methods in measuring the oxygen status in the tumour microenvironment have allowed for a better understanding of the role of hypoxia and how it contributes to tumour progression and treatment resistance. These methods include non-invasive imaging techniques as well as validated hypoxic molecular signatures. Specific hypoxia-targeted therapies have not matched their expectations but may have potential application in combination with traditional treatment approaches in gastroesophageal cancer.