Non-coding RNAs shuttled via exosomes reshape the hypoxic tumor microenvironment

Abstract

Exosomes are small extracellular vesicles secreted by almost all the cells. Molecular cargos of exosomes can partially reflect the characteristics of originating cells. Exosome-mediated cell-to-cell interactions in the microenvironment are critical in cancer progression. Hypoxia, a key pro-cancerous feature of the tumor microenvironment, alters the releasing and contents of exosomes. A growing body of evidence shows that hypoxia induces more aggressive phenotypes in cancer. Of note, non-coding RNAs shuttled in hypoxic tumor-derived exosomes have been demonstrated as fundamental molecules in regulating cancer biology and remodeling tumor microenvironment. Furthermore, these hypoxic tumor-derived exosomal non-coding RNAs can be detected in the body fluids, serving as promising diagnostic and prognostic biomarkers. The current review discusses changes in cancer behaviors regulated by exosomes-secreted non-coding RNAs under hypoxic conditions.

Keywords: Exosomes; Hypoxia; LncRNA; MiRNA; Non-coding RNA; Tumor microenvironment.

Fig. 1

Hypoxia influences the secretion and non-coding RNA cargos of exosomes. Legend: Extracellular components enter cells through endocytosis along with the plasma membrane, leading to the formation of early endosomes and late endosomes (MVBs). Some molecules like ESCRT machinery, ALIX, tetraspanins, and ceramides are involved in this process. Several Rab GTPases are associated with MVBs transporting to the plasma membrane. Then, exosomes with specific cargos are released through exocytosis. Hypoxia triggers the alteration in gene expression of HIFs or other signaling pathways, which may impact exosome biogenesis and cargo sorting by regulating these molecules. Besides, non-coding RNAs binding with some RNA binding proteins like hnRNPA2B1, YB1, NSNU2, or Ago2 might be favorably sorted into exosomes

Fig. 2

Exosomal non-coding RNAs regulate the hypoxic tumor microenvironment. Legend: Hypoxic donor cells impact recipient cells by transmitting non-coding RNAs via exosomes. These exosomal non-coding RNAs can be uptaken by recipient cells and alter their biological behaviors through various pathways, thus regulating tumor development

Fig. 3

Hypoxic tumor-derived circulating exosomal non-coding RNAs in liquid biopsy. Legend: Exosomes are present in diverse biofluids including blood, cerebrospinal fluids, saliva, milk, peritoneal fluid, urine, and synovial fluid. Exosomes can be isolated from these biofluids, and non-coding RNAs are then analyzed for diagnostic or prognosis markers. As illustrated on the right side of the figure, various methods have been developed to isolate exosomes with different advantages and disadvantages each (ultracentrifugation: high sample capacity, minor impacts on exosomal components; time consuming, facility dependent. Polymer-based precipitation reagents: simple steps, possible for small sample volume, high yield; expensive reagents, low purity; immunoaffinity capture: high purity and specificity; expensive reagent, low yield, antibody dependent; density gradient separation: high purity; complicated procedures, low yield, facility dependent. Ultrafiltration: less time consuming; low purity and integrity)