Tumor-derived exosomes in hypoxic microenvironment: release mechanism, biological function and clinical application

Abstract

Hypoxia is a key feature of solid tumors and is related to disease aggressiveness and adverse outcomes. It is recognized that the two-way communication between cancer cells and their microenvironment is critical to cancer progression. Increasing evidences show that the cellular communication and crosstalk between tumor cells and their microenvironment is not limited to secreted molecules, but also includes exosomes secreted by tumor cells. Exosomes are nano-scale extracellular vesicles (30-100 nm in diameter), which carry the molecular characteristics and cargo of the source cell, participating in intercellular communication through autocrine, paracrine and near-crine pathways. Recent studies have shown that cancer cells produce more exosomes under hypoxic conditions than normoxia conditions. The secretion and function of exosomes could be influenced by hypoxia in various types of cancer. Therefore, in this review, we summarize and discuss the latest research on the physiological mechanism of hypoxia regulating the secretion of exosomes, and the involvement of hypoxic exosomes in cancer progression and immune escape processes, and expounds the potential for targeting hypoxia-induced exosomes for cancer therapy strategies.

Keywords: Biological functions; Cancer; Cancer therapy; Exosomes; Hypoxic microenvironment.

Figure 1

Hypoxia in the regulation of exosome secretion. Hypoxia regulates exosomal secretion by affecting processes such as Rab5, Rab22a, Rab27a, ceremides and ALIX/ESCRT.

Figure 2

Hypoxia-induced exosomes influence cancer immune system. The solid red line represents the promoting effect, and the dotted blue line represents the inhibitory effect. Hypoxia promotes the release of exosomes from cancer cells, thereby inhibiting the function of NK cells and inducing the differentiation of macrophages and T cells.