Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2021; 27(28): 4582-4602
Published online Jul 28, 2021. doi: 10.3748/wjg.v27.i28.4582
Modulation of cell physiology under hypoxia in pancreatic cancer
Matias Estaras, Antonio Gonzalez
Matias Estaras, Department of Physiology, Institute of Molecular Pathology Biomarkers, University of Extremadura, Caceres 10003, Spain
Antonio Gonzalez, Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Caceres 10003, Spain
Author contributions: Estaras M prepared parts of the paper, revised and corrected the manuscript, and approved the final version submitted; Gonzalez A provide the conception and design of the manuscript, wrote parts of the paper, revised and corrected the text, and approved the final version submitted.
Supported by Ministerio de Economía y Competitividad, No. BFU2016-79259-R; Junta de Extremadura-FEDER, No. GR18070; and Valhondo Calaff Foundation.
Conflict-of-interest statement: The authors declare that they have no conflicting 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: Antonio Gonzalez, DVM, Full Professor, Department of Physiology, Cell Biology and Communication Research Group, University of Extremadura, Ave Ciencias s/n, Caceres 10003, Spain.
Received: January 28, 2021
Peer-review started: January 28, 2021
First decision: May 2, 2021
Revised: May 28, 2021
Accepted: June 22, 2021
Article in press: June 22, 2021
Published online: July 28, 2021

In solid tumors, the development of vasculature is, to some extent, slower than the proliferation of the different types of cells that form the tissue, both cancer and stroma cells. As a consequence, the oxygen availability is compromised and the tissue evolves toward a condition of hypoxia. The presence of hypoxia is variable depending on where the cells are localized, being less extreme at the periphery of the tumor and more severe in areas located deep within the tumor mass. Surprisingly, the cells do not die. Intracellular pathways that are critical for cell fate such as endoplasmic reticulum stress, apoptosis, autophagy, and others are all involved in cellular responses to the low oxygen availability and are orchestrated by hypoxia-inducible factor. Oxidative stress and inflammation are critical conditions that develop under hypoxia. Together with changes in cellular bioenergetics, all contribute to cell survival. Moreover, cell-to-cell interaction is established within the tumor such that cancer cells and the microenvironment maintain a bidirectional communication. Additionally, the release of extracellular vesicles, or exosomes, represents short and long loops that can convey important information regarding invasion and metastasis. As a result, the tumor grows and its malignancy increases. Currently, one of the most lethal tumors is pancreatic cancer. This paper reviews the most recent advances in the knowledge of how cells grow in a pancreatic tumor by adapting to hypoxia. Unmasking the physiological processes that help the tumor increase its size and their regulation will be of major relevance for the treatment of this deadly tumor.

Keywords: Hypoxia, Cancer, Tumor, Pancreas, Proliferation, Cell survival

Core Tip: Pancreatic ductal adenocarcinoma is characterized by high aggressiveness, therapeutic resistance, and mortality. The cells included in the mass, both tumor and those forming the stroma, have a high proliferative rate that leads to the rapid growth of the tumor. Because of this, the distribution of blood vessels is insufficient to supply oxygen to the cells, and hypoxia is a consequence. Cells escape from death and adapt by undergoing critical changes in intracellular pathways involved in energy supply, proliferation, and cell-to-cell communication.