Microenvironmental pH and Exosome Levels Interplay in Human Cancer Cell Lines of Different Histotypes

Logozzi, Mariantonia; Mizzoni, Davide; Angelini, Daniela F.; Raimo, Rossella Di; Falchi, Mario; Battistini, Luca; Fais, Stefano

doi:10.3390/cancers10100370

Cited by 172 publications

(150 citation statements)

References 44 publications

(83 reference statements)

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“…[44] In this study, we followed recommended MISEV 2018 guidelines to characterize the isolated serum small vesicles. [50] Alternate method, nanoscale flow cytometry, could also generate both the size and EVs markers expression in gated subpopulations. [46] A subset of samples used for validation was used for isolating small EVs using ultracentrifugation sucrose density gradient method.…”

Section: Discussionmentioning

confidence: 99%

Serum Small Extracellular Vesicles Proteome of Tuberculosis Patients Demonstrated Deregulated Immune Response

Arya

Dabral

Faruquee

et al. 2019

Proteomics Clinical Apps

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Purpose Detailed understanding of host pathogen interaction in tuberculosis is an important avenue for identifying novel therapeutic targets. Small extracellular vesicles (EVs) like exosomes that are rich in proteins, nucleic acids and lipids, act as messengers and may show altered composition in disease conditions. Experimental design In this case control study, small EVs are isolated from serum of 58 subjects (all male, 33 (15–70) in years) including drug naïve active tuberculosis (ATB: n = 22), non‐tuberculosis (NTB: n = 18), and healthy subjects (n = 18). Serum small EVs proteome analysis is carried out using isobaric tag for relative and absolute quantification (iTRAQ) experiments and an independent sample (n = 36) is used for validation. Results A set of 132 and 68 proteins are identified in iTRAQ‐I (ATB/Healthy) and iTRAQ‐II (ATB/NTB) experiments, respectively. Four proteins (KYAT3, SERPINA1, HP, and APOC3) show deregulation (log2‐fold change > ±0.48, p < 0.05) in ATB with respect to healthy controls and Western blot data corroborated mass spectrometry findings. Conclusions and clinical relevance These important proteins, involved in neutrophil degranulation, plasma heme scavenging, kynurenine, and lipid metabolism, show deregulation in ATB patients. Identification of such a protein panel in circulating small EVs besides providing novel insights into their role in tuberculosis may prove to be useful targets to develop host‐directed therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Serum Small Extracellular Vesicles Proteome of Tuberculosis Patients Demonstrated Deregulated Immune Response

Arya

Dabral

Faruquee

et al. 2019

Proteomics Clinical Apps

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“…Recently, our groups showed that the tumour acidic microenvironment markedly increases the number of exosomes, also those expressing CA IX 16,17,30 . However, never the acidity of the tumour microenvironment has been associated with the intraluminal acidification of the exosome released by cancer cells.…”

Section: Exosomes From Pca Plasma Patients Are Acidicmentioning

confidence: 99%

“…Therefore, tumour cells up-regulate proton exchangers and transporters throwing out excess protons through Vacuolar ATPase (V-ATPase), Naþ/H þ exchanger (NHE), monocarboxylate transporters (MCTs), cotransporter sodium bicarbonate (NBC), and carbonic anhydrase 9 (CA IX) 2,[11][12][13] . Chemoresistance of cancers and the increase in exosome release are two well-known effects of the extracellular acidification [14][15][16][17][18] . Exosomes are extracellular nanovesicles of 40-180 nm secreted by all cells and capable of modulating physiological or pathological processes, including tumour progression, through transmitting into target cells their cargo (lipids, proteins, DNA, mRNA or microRNA) [18][19][20][21][22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

“…High plasmatic levels of extracellular vesicles are related with the tumour mass 28,29 . It has been demonstrated that, independently from the tumour histotype, the tumour cell lines cultured at pH 6.5 released significantly higher levels of exosomes as compared to the same cells cultured at physiological pH (7.4) 16,17 . Recently, it has been shown that the microenvironmental low pH was consistent with a change in exosome cargo as well as with some tumour biomarkers such as Prostate Specific Antigen (PSA) and carbonic anhydrase (CA) IX 16,30 .…”

Section: Introductionmentioning

confidence: 99%

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Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH

Logozzi

Mizzoni

Capasso

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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2020) Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH, Journal of Enzyme Inhibition and Medicinal Chemistry, 35:1, 280-288, 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.

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“…Thus, we cultured cells of the human breast cancer cell line MDA-MB-231, both at a standard pH of 7.5 and at a low, slightly acidic pH of 6.5, which is representative of average tumor acidity. 39 We fluorescently labeled magnetosomes with and without expression of pHLIP using a lipophilic membrane dye (DiI) inserted into the membrane of the magnetosome. We incubated both wild-type and pHLIP-functionalized magnetosomes with MDA-MB-231 cells at low pH and standard pH and analyzed the binding efficiency by flow cytometry.…”

Section: Peptide-fused Magnetosomes Serve As Functional Binding Agentsmentioning

confidence: 99%

Genetic encoding of targeted MRI contrast agents for in vivo tumor imaging

Schuerle¹,

Furubayashi

Soleimany

et al. 2019

Preprint

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Tumor-selective contrast agents have the potential to aid in the diagnosis and treatment of cancer using noninvasive imaging modalities such as magnetic resonance imaging (MRI). Such contrast agents can consist of magnetic nanoparticles incorporating functionalities that respond to cues specific to tumor environments. Genetically engineering magnetotactic bacteria to display peptides has been investigated as a means to produce contrast agents that combine the robust image contrast effects of magnetosomes with transgenic targeting peptides displayed on their surface. This work reports the first use of magnetic nanoparticles that display genetically-encoded pH low insertion peptide (pHLIP), a long peptide intended to enhance MRI contrast by targeting the extracellular acidity associated with the tumors. To demonstrate the modularity of this versatile platform to incorporate diverse targeting ligands by genetic engineering, we also incorporated the cyclic αv integrin-binding peptide iRGD into separate magnetosomes. Specifically, we investigate their potential for enhanced binding and tumor imaging both in vitro and in vivo. Our experiments indicate that these tailored magnetosomes retain their magnetic properties, making them well-suited as T2 contrast agents, while exhibiting increased binding compared to wild-type magnetosomes.

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Microenvironmental pH and Exosome Levels Interplay in Human Cancer Cell Lines of Different Histotypes

Cited by 172 publications

References 44 publications

Serum Small Extracellular Vesicles Proteome of Tuberculosis Patients Demonstrated Deregulated Immune Response

Serum Small Extracellular Vesicles Proteome of Tuberculosis Patients Demonstrated Deregulated Immune Response

Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH

Genetic encoding of targeted MRI contrast agents for in vivo tumor imaging

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