Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles
Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that hypoxic tumours synthesize hypoxia-sensitive proteins for...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/10/2917 |
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| author | Shun Wilford Tse Chee Fan Tan Jung Eun Park JebaMercy Gnanasekaran Nikhil Gupta Jee Keem Low Kheng Wei Yeoh Wee Joo Chng Chor Yong Tay Neil E. McCarthy Sai Kiang Lim Siu Kwan Sze |
| author_facet | Shun Wilford Tse Chee Fan Tan Jung Eun Park JebaMercy Gnanasekaran Nikhil Gupta Jee Keem Low Kheng Wei Yeoh Wee Joo Chng Chor Yong Tay Neil E. McCarthy Sai Kiang Lim Siu Kwan Sze |
| author_sort | Shun Wilford Tse |
| collection | DOAJ |
| description | Extracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that hypoxic tumours synthesize hypoxia-sensitive proteins for packing into EVs to modulate their microenvironment for cancer progression. In the current report, we employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia sensitive proteins in tumour-derived EVs protein. The results revealed that hypoxia stimulated cells to synthesize EVs proteins involved in enhancing tumour cell proliferation (NRSN2, WISP2, SPRX1, LCK), metastasis (GOLM1, STC1, MGAT5B), stemness (STC1, TMEM59), angiogenesis (ANGPTL4), and suppressing host immunity (CD70). In addition, functional clustering analyses revealed that tumour hypoxia was strongly associated with rapid synthesis and EV loading of lysosome-related hydrolases and membrane-trafficking proteins to enhance EVs secretion. Moreover, lung cancer-derived EVs were also enriched in signalling molecules capable of inducing epithelial-mesenchymal transition in recipient cancer cells to promote their migration and invasion. Together, these data indicate that lung-cancer-derived EVs can act as paracrine/autocrine mediators of tumorigenesis and metastasis in hypoxic microenvironments. Tumour EVs may, therefore, offer novel opportunities for useful biomarkers discovery and therapeutic targeting of different cancer types and at different stages according to microenvironmental conditions. |
| first_indexed | 2024-03-10T15:43:29Z |
| format | Article |
| id | doaj.art-78841469fcb84752a66d3a71a4adf607 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T15:43:29Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-78841469fcb84752a66d3a71a4adf6072023-11-20T16:38:04ZengMDPI AGCancers2072-66942020-10-011210291710.3390/cancers12102917Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular VesiclesShun Wilford Tse0Chee Fan Tan1Jung Eun Park2JebaMercy Gnanasekaran3Nikhil Gupta4Jee Keem Low5Kheng Wei Yeoh6Wee Joo Chng7Chor Yong Tay8Neil E. McCarthy9Sai Kiang Lim10Siu Kwan Sze11School of Biological Sciences, Nanyang Technological University, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, Singapore 637551, SingaporeDepartment of Surgery, Tan Tock Seng Hospital, Singapore 308433, SingaporeDepartment of Radiation Oncology, National Cancer Centre Singapore, Singapore 169610, SingaporeDepartment of Hematology-Oncology, National University Cancer Institute, National University Health System, Singapore 119228, SingaporeSchool of Materials Science and Engineering, Nanyang Technological University, Singapore 639798, SingaporeCentre for Immunobiology, The Blizard Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UKInstitute of Medical Biology, Singapore 138648, SingaporeSchool of Biological Sciences, Nanyang Technological University, Singapore 637551, SingaporeExtracellular vesicles (EVs) mediate critical intercellular communication within healthy tissues, but are also exploited by tumour cells to promote angiogenesis, metastasis, and host immunosuppression under hypoxic stress. We hypothesize that hypoxic tumours synthesize hypoxia-sensitive proteins for packing into EVs to modulate their microenvironment for cancer progression. In the current report, we employed a heavy isotope pulse/trace quantitative proteomic approach to study hypoxia sensitive proteins in tumour-derived EVs protein. The results revealed that hypoxia stimulated cells to synthesize EVs proteins involved in enhancing tumour cell proliferation (NRSN2, WISP2, SPRX1, LCK), metastasis (GOLM1, STC1, MGAT5B), stemness (STC1, TMEM59), angiogenesis (ANGPTL4), and suppressing host immunity (CD70). In addition, functional clustering analyses revealed that tumour hypoxia was strongly associated with rapid synthesis and EV loading of lysosome-related hydrolases and membrane-trafficking proteins to enhance EVs secretion. Moreover, lung cancer-derived EVs were also enriched in signalling molecules capable of inducing epithelial-mesenchymal transition in recipient cancer cells to promote their migration and invasion. Together, these data indicate that lung-cancer-derived EVs can act as paracrine/autocrine mediators of tumorigenesis and metastasis in hypoxic microenvironments. Tumour EVs may, therefore, offer novel opportunities for useful biomarkers discovery and therapeutic targeting of different cancer types and at different stages according to microenvironmental conditions.https://www.mdpi.com/2072-6694/12/10/2917extracellular vesicleshypoxiatumour microenvironmentepithelial–mesenchymal transitiontumorigenesispulsed-SILAC |
| spellingShingle | Shun Wilford Tse Chee Fan Tan Jung Eun Park JebaMercy Gnanasekaran Nikhil Gupta Jee Keem Low Kheng Wei Yeoh Wee Joo Chng Chor Yong Tay Neil E. McCarthy Sai Kiang Lim Siu Kwan Sze Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles Cancers extracellular vesicles hypoxia tumour microenvironment epithelial–mesenchymal transition tumorigenesis pulsed-SILAC |
| title | Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles |
| title_full | Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles |
| title_fullStr | Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles |
| title_full_unstemmed | Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles |
| title_short | Microenvironmental Hypoxia Induces Dynamic Changes in Lung Cancer Synthesis and Secretion of Extracellular Vesicles |
| title_sort | microenvironmental hypoxia induces dynamic changes in lung cancer synthesis and secretion of extracellular vesicles |
| topic | extracellular vesicles hypoxia tumour microenvironment epithelial–mesenchymal transition tumorigenesis pulsed-SILAC |
| url | https://www.mdpi.com/2072-6694/12/10/2917 |
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