Abstract
Acidity, hypoxia and increased release of exosomes are severe phenotypes of tumours. The regulation of pH in tumours involves the interaction of several proteins, including the carbonic anhydrases which catalyze the formation of bicarbonate and protons from carbon dioxide and water. Among CA isoforms, CA IX is over-expressed in a large number of solid tumours, conferring to cancer cells a survival advantage in hypoxic and acidic microenvironment, but there isn’t evidence that CA IX expression could have a real clinical impact. Therefore, in this study for the first time the expression and activity of CA IX have been investigated in the plasmatic exosomes obtained from patients with prostate carcinoma (PCa). For this purpose, the study was performed through different methodological approaches, such as NTA, western blot analysis, enzyme activity assay, Nanoscale flow cytometry, ELISA, confocal microscopy. The results showed that PCa exosomes significantly overexpressed CA IX levels and related activity as compared to healthy donors. Furthermore, CA IX expression and activity were correlated to the exosome intraluminal pH, demonstrating for the first time that PCa exosomes are acidic. Our data suggest the possible use of the exosomal CA IX expression and activity as a biomarker of cancer progression in PCa.
Highlights
Extracellular acidity is a common phenotype of malignant tumours due to the “Warburg effect”
The results showed that carbonic anhydrase (CA) IX expression was up-regulated in exosomal purification lysates from prostate cancer (PCa) plasma patients (Figure 2(A)) as compared to the exosomal fractions of CTR plasma (Figure 2(B))
The results showed that the CA-activity/mg protein found in exosomes isolated from PCa plasma (2.9 ± 0.4) was 2.4-fold higher as compared to exosomes purified from CTR plasma (1.2 ± 0.2) (p < .0001) (Figure 4); supporting that the increased CA IX expression in plasmatic exosomes of PCa patients was consistent with a real enzyme activity up-regulated in PCa plasma exosomes
Summary
Extracellular acidity is a common phenotype of malignant tumours due to the “Warburg effect”. The extracellular acidity induces a selective pressure leading to the clonal selection of cancer cells that can survive in such a hostile condition[7]. Cancer cells survive and proliferate thanks to a series of innate mechanism conceivably common to all malignant tumours[8,9,10]. Chemoresistance of cancers and the increase in exosome release are two well-known effects of the extracellular acidification[14,15,16,17,18]. The acid release of the exosomes is key in tumour growth, tumour progression and metastasis[18,24,27]. It has been demonstrated that, independently from the tumour histotype, the tumour cell lines cultured at pH
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