Impact of hypoxia on the molecular content of glioblastoma-derived exosomes

Abstract

Hypoxia is a pathologic condition characterized by a tissue oxygen deficiency due to either decreased oxygen intake from outside and/or disruption of oxygen utilization in cells. This condition may arise when the oxygen demand exceeds its supply or the partial pressure of oxygen is below 10 mmHg. This situation poses a significant problem for glioblastoma (GBM) patients as it can activate angiogenesis, increase invasiveness and metastatic risk, prolong tumor survival, and suppress anti-tumor immunity, making hypoxic cells resistant to radiotherapy and chemotherapy. Low oxygen levels in tumors can cause severe cellular changes that can affect the release of extracellular vesicles (EVs), especially exosomes (EXOs), altering their proteomic profile both qualitatively and quantitatively. EXOs represent an adaptive response to hypoxic stress; therefore, they can be used to determine oxygen levels in cancer and assess its aggressiveness. They not only release signaling molecules to attract cells that promote the formation of small vessel walls but also send signals to other tumor cells that trigger their migration, which in turn plays a crucial role in the formation of metastases under hypoxia. This review investigates how the molecular profile of GBM-derived exosomes changes under hypoxic conditions, offering future possibilities for noninvasive diagnosis and monitoring of brain tumor patients.

Keywords: HIF-1α; Hypoxia; exosomes; extracellular vesicles; glioblastoma; noninvasive biomarker.

Figure 1

GBM tumor microenvironment. The abnormal neovascularization, due to uncontrolled tumor growth, leads to poor oxygen diffusion and hypoxic regions in the tumor mass, promoting the expression of HIF-1α. This mediator of hypoxia is responsible for the regulation of various processes, including angiogenesis, by enhancing the levels of VEGF that, in turn, act as an inducer of mitogenesis and migration of endothelial cells. This process leads to “cyclic hypoxia” characterized by a dynamic phase of hypoxia and reoxygenation within the tumor mass. Moreover, HIFs have been shown to promote EXOs biogenesis and secretion, promoting cancer metastasis and therapy resistance by mediating both the migration of glioma cells and the proliferation and migration of endothelial cells. Figure was created with https://www.biorender.com/. GBM: glioblastoma; HIF: hypoxia-inducible factor; VEGF: vascular endothelial growth factor; EXOs: exosomes.

Figure 2

The generation of EVs and the characteristics of hypoxia-induced EVs in the recipient cells. EXOs originate within MVBs by budding into the endosomal membrane, resulting in the release of small vesicles within this compartment. MVBs fuse with the cell membrane to release EXOs into the extracellular space, while MVs form directly from the outward shedding of the plasma membrane. Both EVs types carry diverse cargos, including DNA, mRNA, ncRNA, proteins, and metabolites. In hypoxic cells, there is an increased release of exosomes, which play a multitude of roles upon reaching the recipient cells. Hypoxic EVs play roles in invasion, migration, angiogenesis, proliferation, immune responses, and drug resistance of cancer cells. Figure was created with https://www.biorender.com/. mRNA: messenger RNA; ncRNA: noncoding RNA; EVs: extracellular vesicles; EXOs: exosomes; MVBs: multivesicular bodies.