Abstract
Large oncosomes (LO) are atypically large (1-10 µm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrep(TM)) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5th percentile) and was used to develop an assay to detect LO in the circulation and tissues of mice and patients with prostate cancer. These observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers.
Highlights
Extracellular vesicles (EVs) that originate from cancer cells are gradually and consistently emerging as important regulators of tumor progression[1]
Consistent with published results, silencing of the cytoskeletal regulator Diaphanous-related formin-3 (DIAPH3) in DU145 cells resulted in the formation of large plasma membrane blebs (1-10 μm in diameter) (Figure 1A, Supplementary Movie 1) [8, 10], which were shed into the medium as large EVs (Figure 1B)
We observed a significant increase in the mean fluorescent intensity (MFI) of the cytokeratin 18 (CK18) signal in the plasma EVs of mice injected with shDIAPH3 DU145 cells in comparison to mice injected with control cells (Figure 6A)
Summary
Extracellular vesicles (EVs) that originate from cancer cells are gradually and consistently emerging as important regulators of tumor progression[1]. After years of research aimed to identify unequivocal exosome markers, it is clear that “universal exosome markers” are difficult to find, and recent proteomic studies suggest that exosome populations are diverse and can be enriched with distinct proteins that impart specific functions to the particles[7]. It is not known whether specific proteins can be expressed in exosomes versus plasma membrane-derived EVs, such as ectosomes/MVs, and vice-versa
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