Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling
Abstract Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer development. COPD induces activation of hypoxia-induced signaling, causing remodeling of surrounding microenvironmental cells also modulating the release and cargo of their extracellular vesicles (EVs). We aimed t...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06212-1 |
| _version_ | 1827793525279817728 |
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| author | Ilaria Petraroia Patrizia Ghidotti Giulia Bertolini Francesca Pontis Luca Roz Melissa Balsamo Paola Suatoni Ugo Pastorino Anna Maria Ferretti Gabriella Sozzi Orazio Fortunato |
| author_facet | Ilaria Petraroia Patrizia Ghidotti Giulia Bertolini Francesca Pontis Luca Roz Melissa Balsamo Paola Suatoni Ugo Pastorino Anna Maria Ferretti Gabriella Sozzi Orazio Fortunato |
| author_sort | Ilaria Petraroia |
| collection | DOAJ |
| description | Abstract Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer development. COPD induces activation of hypoxia-induced signaling, causing remodeling of surrounding microenvironmental cells also modulating the release and cargo of their extracellular vesicles (EVs). We aimed to evaluate the potential role of circulating EVs from COPD subjects in lung cancer onset. Plasma-EVs were isolated by ultracentrifugation from heavy smoker volunteers with (COPD-EVs) or without (heavy smoker-EVs, HS-EV) COPD and characterized following MISEV guidelines. Immortalized human bronchial epithelial cells (CDK4, hTERT-HBEC3-KT), genetically modified with different oncogenic alterations commonly found in lung cancer (sh-p53, KRASV12), were used to test plasma-EVs pro-tumorigenic activity in vitro. COPD-EVs mainly derived from immune and endothelial cells. COPD-EVs selectively increased the subset of CD133+CXCR4+ metastasis initiating cells (MICs) in HBEC-sh-p53-KRASV12high cells and stimulated 3D growth, migration/invasion, and acquisition of mesenchymal traits. These effects were not observed in HBEC cells bearing single oncogenic mutation (sh-p53 or KRASV12). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transferred from COPD-EVs triggers CXCR4 pathway activation that in turn mediates MICs expansion and acquisition of pro-tumorigenic effects. Indeed, HIF-1α inhibition or CXCR4 silencing prevented the acquisition of malignant traits induced by COPD-EVs alone. Hypoxia recapitulates the effects observed with COPD-EVs in HBEC-sh-p53-KRASV12high cells. Notably, higher levels of HIF-1α were observed in EVs from COPD subjects who subsequently developed cancer compared to those who remained cancer-free. Our findings support a role of COPD-EVs to promote the expansion of MICs in premalignant epithelial cells through HIF-1α-CXCR4 axis activation thereby potentially sustaining lung cancer progression. |
| first_indexed | 2024-03-11T18:20:43Z |
| format | Article |
| id | doaj.art-027a0899ef564e3680a7749293ab561f |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-11T18:20:43Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-027a0899ef564e3680a7749293ab561f2023-10-15T11:30:23ZengNature Publishing GroupCell Death and Disease2041-48892023-10-01141011210.1038/s41419-023-06212-1Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttlingIlaria Petraroia0Patrizia Ghidotti1Giulia Bertolini2Francesca Pontis3Luca Roz4Melissa Balsamo5Paola Suatoni6Ugo Pastorino7Anna Maria Ferretti8Gabriella Sozzi9Orazio Fortunato10Epigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei TumoriEpigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei TumoriEpigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei TumoriEpigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei TumoriEpigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei TumoriEpigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei TumoriThoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei TumoriThoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale dei TumoriIstituto di Scienze e Tecnologie Chimiche-CNREpigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei TumoriEpigenomics and biomarkers of solid tumors, Fondazione IRCCS Istituto Nazionale dei TumoriAbstract Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer development. COPD induces activation of hypoxia-induced signaling, causing remodeling of surrounding microenvironmental cells also modulating the release and cargo of their extracellular vesicles (EVs). We aimed to evaluate the potential role of circulating EVs from COPD subjects in lung cancer onset. Plasma-EVs were isolated by ultracentrifugation from heavy smoker volunteers with (COPD-EVs) or without (heavy smoker-EVs, HS-EV) COPD and characterized following MISEV guidelines. Immortalized human bronchial epithelial cells (CDK4, hTERT-HBEC3-KT), genetically modified with different oncogenic alterations commonly found in lung cancer (sh-p53, KRASV12), were used to test plasma-EVs pro-tumorigenic activity in vitro. COPD-EVs mainly derived from immune and endothelial cells. COPD-EVs selectively increased the subset of CD133+CXCR4+ metastasis initiating cells (MICs) in HBEC-sh-p53-KRASV12high cells and stimulated 3D growth, migration/invasion, and acquisition of mesenchymal traits. These effects were not observed in HBEC cells bearing single oncogenic mutation (sh-p53 or KRASV12). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transferred from COPD-EVs triggers CXCR4 pathway activation that in turn mediates MICs expansion and acquisition of pro-tumorigenic effects. Indeed, HIF-1α inhibition or CXCR4 silencing prevented the acquisition of malignant traits induced by COPD-EVs alone. Hypoxia recapitulates the effects observed with COPD-EVs in HBEC-sh-p53-KRASV12high cells. Notably, higher levels of HIF-1α were observed in EVs from COPD subjects who subsequently developed cancer compared to those who remained cancer-free. Our findings support a role of COPD-EVs to promote the expansion of MICs in premalignant epithelial cells through HIF-1α-CXCR4 axis activation thereby potentially sustaining lung cancer progression.https://doi.org/10.1038/s41419-023-06212-1 |
| spellingShingle | Ilaria Petraroia Patrizia Ghidotti Giulia Bertolini Francesca Pontis Luca Roz Melissa Balsamo Paola Suatoni Ugo Pastorino Anna Maria Ferretti Gabriella Sozzi Orazio Fortunato Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling Cell Death and Disease |
| title | Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling |
| title_full | Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling |
| title_fullStr | Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling |
| title_full_unstemmed | Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling |
| title_short | Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling |
| title_sort | extracellular vesicles from subjects with copd modulate cancer initiating cells phenotype through hif 1α shuttling |
| url | https://doi.org/10.1038/s41419-023-06212-1 |
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