Microenvironmental pH Is a Key Factor for Exosome Traffic in Tumor Cells*

By I. Parolini, C. Federici, C. Raggi, L. Lugini, S. Palleschi, A. De Milito, C. Coscia, Elisabetta Iessi, M. Logozzi, A. Molinari and 4 more. Journal of Biological Chemistry, 2009

1,413 citations recorded by the source corpus.

Exosomes secreted by normal and cancer cells carry and deliver a variety of molecules. To date, mechanisms referring to tumor exosome trafficking, including release and cell-cell transmission, have not been described. To gain insight into this, exosomes purified from metastatic melanoma cell medium were labeled with a lipid fluorescent probe, R18, and analyzed by spectrofluorometry and confocal microscopy. A low pH condition is a hallmark of tumor malignancy, potentially influencing exosome release and uptake by cancer cells. Using different pH conditions as a modifier of exosome traffic, we showed (i) an increased exosome release and uptake at low pH when compared with a buffered condition and (ii) exosome uptake by melanoma cells occurred by fusion. Membrane biophysical analysis, such as fluidity and lipid composition, indicated a high rigidity and sphingomyelin/ganglioside GM3 (N-acetylneuraminylgalactosylglucosylceramide) content in exosomes released at low pH. This was likely responsible for the increased fusion efficiency. Consistent with these results, pretreatment with proton pump inhibitors led to an inhibition of exosome uptake by melanoma cells. Fusion efficiency of tumor exosomes resulted in being higher in cells of metastatic origin than in those derived from primary tumors or normal cells. Furthermore, we found that caveolin-1, a protein involved in melanoma progression, is highly delivered through exosomes released in an acidic condition. The results of our study provide the evidence that exosomes may be used as a delivery system for paracrine diffusion of tumor malignancy, in turn supporting the importance of both exosomes and tumor pH as key targets for future anti-cancer strategies.

Subfields: Biomedical Engineering, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0352814cc631e6e24f50f22fa44f7cecf4834713

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Citations in the corpus

Tetraspanins in Extracellular Vesicle Formation and Function (2014, background): “the fusion of exosomes with the plasma membrane of recipient cells it is difficult at a neutral pH (118).”
Advances in therapeutic applications of extracellular vesicles (2019, background): “EVs have been suggested to be internalized into target cells by various uptake mechanisms including membrane fusion (171) and different endocytic pathways including phagocytosis (172), receptor-mediated endocytosis (173), lipid raft–mediated endocytosis (174), clathrin-mediated endocytosis (175), ca”
Exosomes in Cancer Development, Metastasis and Drug Resistance: A Comprehensive Review (2013, positive): “Exosome release has been shown to be triggered by various other stimuli as well as including ceramide [44] and changes in membrane pH [45].”
Extracellular Vesicles: Unique Intercellular Delivery Vehicles. (2017, background): “In addition, acidic pH in the extracellular environment has also been shown to enhance EV-membrane fusion [58], suggesting that EV fusion with the plasma membrane may occur preferentially in acidic environments, such as occurs in tumors or in the stomach.”
Exosomes and their roles in immune regulation and cancer. (2015, background): “t has been demonstrated that the low pH of the tumour microenironment is essential for exosome uptake by human metastatic elanoma in vitro, that is suggested to be related to elevated staility and lipid/cholesterol content of exosomal membranes in an cidic environment [28].”
Exosome Theranostics: Biology and Translational Medicine (2018, background): “However, the high level of cholesterol, ganglioside, and sphingomyelin in exosomal membranes leads to a more rigid bilayer structure than that of their parent cells [188], which suggests that their fusion with lipid-based particles requires harsher conditions [189].”