Modulation of cell physiology under hypoxia in pancreatic cancer

Abstract

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.