Abstract
Extracellular vesicles (EVs) released from cancer cells contribute to various malignant phenotypes of cancer, including metastasis, cachexia, and angiogenesis. Although DNA, mRNAs, miRNAs, and proteins contained in EVs have been extensively studied, the function of metabolites in EVs remains unclear. In this study, we performed a comprehensive metabolomic analysis of pancreatic cancer cells, PANC-1, cultured under different oxygen concentrations, and small EVs (sEVs) released from them, considering the fact that hypoxia contributes to the malignant behavior of cells in pancreatic cancer, which is a poorly diagnosed cancer. sEVs were collected by ultracentrifugation, and hydrophilic metabolites were analyzed using capillary ion chromatography-mass spectrometry and liquid chromatography-mass spectrometry, and lipids were analyzed by supercritical fluid chromatography-tandem mass spectrometry. A total of 140 hydrophilic metabolites and 494 lipids were detected in sEVs, and their profiles were different from those in cells. In addition, the metabolomic profile of sEVs was observed to change under hypoxic stress, and an increase in metabolites involved in angiogenesis was also detected. We reveal the hallmark of the metabolites contained in sEVs and the effect of tumor hypoxia on their profiles, which may help in understanding EV-mediated cancer malignancy.
Highlights
Extracellular vesicles (EVs) are lipid bilayer structures with a diameter of less than μm; they include exosomes (50–150 nm) and microvesicles (100–1000 nm) [1]
We isolated the small extracellular vesicles (sEVs) released from PANC-1 cells cultured under conditions of 20% or 1% O2 by ultracentrifugation (234,700 × g for 70 min at 4 ◦C) of 260 mL of conditioned medium
To verify the response to hypoxic stress in cells and sEVs, we examined the expression of genes and microRNAs that have been reported to be upregulated under hypoxia in cells or sEVs [24,26]
Summary
Extracellular vesicles (EVs) are lipid bilayer structures with a diameter of less than μm; they include exosomes (50–150 nm) and microvesicles (100–1000 nm) [1]. EVs are contained in body fluids, such as blood, urine, and saliva, and are present in the supernatant of cultured cells [1]. They play important roles in promoting cancer progression, such as in distant metastasis, proliferation, angiogenesis, and resistance to treatment [2,3,4,5]. EVs contain DNA, mRNAs, miRNAs, proteins, and lipids, and their amounts vary depending on the type of cell and physiological conditions. Some of the hydrophilic metabolites contained in EVs are possibly involved in the malignant transformation of cancer [11], but their details remain unclear
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