Extracellular Vesicle Membrane Protein Profiling and Targeted Mass Spectrometry Unveil CD59 and Tetraspanin 9 as Novel Plasma Biomarkers for Detection of Colorectal Cancer
Extracellular vesicles (EVs) are valuable sources for the discovery of useful cancer biomarkers. This study explores the potential usefulness of tumor cell-derived EV membrane proteins as plasma biomarkers for early detection of colorectal cancer (CRC). EVs were isolated from the culture supernatant...
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| Veröffentlicht in: | Cancers 2022-12, Vol.15 (1), p.177 |
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| creator | Dash, Srinivas Wu, Chia-Chun Wu, Chih-Ching Chiang, Sum-Fu Lu, Yu-Ting Yeh, Chien-Yuh You, Jeng-Fu Chu, Lichieh Julie Yeh, Ta-Sen Yu, Jau-Song |
| description | Extracellular vesicles (EVs) are valuable sources for the discovery of useful cancer biomarkers. This study explores the potential usefulness of tumor cell-derived EV membrane proteins as plasma biomarkers for early detection of colorectal cancer (CRC). EVs were isolated from the culture supernatants of four CRC cell lines by ultracentrifugation, and their protein profiles were analyzed by LC-MS/MS. Bioinformatics analysis of identified proteins revealed 518 EV membrane proteins in common among at least three CRC cell lines. We next used accurate inclusion mass screening (AIMS) in parallel with iTRAQ-based quantitative proteomic analysis to highlight candidate proteins and validated their presence in pooled plasma-generated EVs from 30 healthy controls and 30 CRC patients. From these, we chose 14 potential EV-derived targets for further quantification by targeted MS assay in a separate individual cohort comprising of 73 CRC and 80 healthy subjects. Quantitative analyses revealed significant increases in ADAM10, CD59 and TSPAN9 levels (2.19- to 5.26-fold, p < 0.0001) in plasma EVs from CRC patients, with AUC values of 0.83, 0.95 and 0.87, respectively. Higher EV CD59 levels were significantly correlated with distant metastasis (p = 0.0475), and higher EV TSPAN9 levels were significantly associated with lymph node metastasis (p = 0.0011), distant metastasis at diagnosis (p = 0.0104) and higher TNM stage (p = 0.0065). A two-marker panel consisting of CD59 and TSPAN9 outperformed the conventional marker CEA in discriminating CRC and stage I/II CRC patients from healthy controls, with AUC values of 0.98 and 0.99, respectively. Our results identify EV membrane proteins in common among CRC cell lines and altered plasma EV protein profiles in CRC patients and suggest plasma EV CD59 and TSPAN9 as a novel biomarker panel for detecting early-stage CRC. |
| doi_str_mv | 10.3390/cancers15010177 |
| format | Article |
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This study explores the potential usefulness of tumor cell-derived EV membrane proteins as plasma biomarkers for early detection of colorectal cancer (CRC). EVs were isolated from the culture supernatants of four CRC cell lines by ultracentrifugation, and their protein profiles were analyzed by LC-MS/MS. Bioinformatics analysis of identified proteins revealed 518 EV membrane proteins in common among at least three CRC cell lines. We next used accurate inclusion mass screening (AIMS) in parallel with iTRAQ-based quantitative proteomic analysis to highlight candidate proteins and validated their presence in pooled plasma-generated EVs from 30 healthy controls and 30 CRC patients. From these, we chose 14 potential EV-derived targets for further quantification by targeted MS assay in a separate individual cohort comprising of 73 CRC and 80 healthy subjects. Quantitative analyses revealed significant increases in ADAM10, CD59 and TSPAN9 levels (2.19- to 5.26-fold, p < 0.0001) in plasma EVs from CRC patients, with AUC values of 0.83, 0.95 and 0.87, respectively. Higher EV CD59 levels were significantly correlated with distant metastasis (p = 0.0475), and higher EV TSPAN9 levels were significantly associated with lymph node metastasis (p = 0.0011), distant metastasis at diagnosis (p = 0.0104) and higher TNM stage (p = 0.0065). A two-marker panel consisting of CD59 and TSPAN9 outperformed the conventional marker CEA in discriminating CRC and stage I/II CRC patients from healthy controls, with AUC values of 0.98 and 0.99, respectively. Our results identify EV membrane proteins in common among CRC cell lines and altered plasma EV protein profiles in CRC patients and suggest plasma EV CD59 and TSPAN9 as a novel biomarker panel for detecting early-stage CRC.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers15010177</identifier><identifier>PMID: 36612172</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Antigens ; Bioinformatics ; Biological markers ; Biomarkers ; Biopsy ; Cancer ; Candidates ; CD59 antigen ; Cell culture ; Cell organelles ; Chemotherapy ; Colorectal cancer ; Colorectal carcinoma ; Developing countries ; Diagnosis ; Epidermal growth factor ; Health aspects ; LDCs ; Lymph nodes ; Mass spectrometry ; Mass spectroscopy ; Medical prognosis ; Medical research ; Membrane proteins ; Metastases ; Metastasis ; Methods ; Mortality ; Plasma ; Prostate ; Proteins ; Proteomes ; Proteomics ; Scientific imaging ; Surgery ; Tumor cells ; Ultracentrifugation</subject><ispartof>Cancers, 2022-12, Vol.15 (1), p.177</ispartof><rights>COPYRIGHT 2022 MDPI AG</rights><rights>2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2022 by the authors. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-cb6a24e71cf40c718d02558b8341e8a496806569fddf6c143204b7cf2aa396cf3</citedby><cites>FETCH-LOGICAL-c488t-cb6a24e71cf40c718d02558b8341e8a496806569fddf6c143204b7cf2aa396cf3</cites><orcidid>0000-0002-5962-6185 ; 0000-0001-8753-0239 ; 0000-0002-4295-983X ; 0000-0002-8488-9614 ; 0000-0002-7264-9672 ; 0000-0001-5748-1659 ; 0000-0001-7684-1285</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818822/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9818822/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36612172$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dash, Srinivas</creatorcontrib><creatorcontrib>Wu, Chia-Chun</creatorcontrib><creatorcontrib>Wu, Chih-Ching</creatorcontrib><creatorcontrib>Chiang, Sum-Fu</creatorcontrib><creatorcontrib>Lu, Yu-Ting</creatorcontrib><creatorcontrib>Yeh, Chien-Yuh</creatorcontrib><creatorcontrib>You, Jeng-Fu</creatorcontrib><creatorcontrib>Chu, Lichieh Julie</creatorcontrib><creatorcontrib>Yeh, Ta-Sen</creatorcontrib><creatorcontrib>Yu, Jau-Song</creatorcontrib><title>Extracellular Vesicle Membrane Protein Profiling and Targeted Mass Spectrometry Unveil CD59 and Tetraspanin 9 as Novel Plasma Biomarkers for Detection of Colorectal Cancer</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Extracellular vesicles (EVs) are valuable sources for the discovery of useful cancer biomarkers. This study explores the potential usefulness of tumor cell-derived EV membrane proteins as plasma biomarkers for early detection of colorectal cancer (CRC). EVs were isolated from the culture supernatants of four CRC cell lines by ultracentrifugation, and their protein profiles were analyzed by LC-MS/MS. Bioinformatics analysis of identified proteins revealed 518 EV membrane proteins in common among at least three CRC cell lines. We next used accurate inclusion mass screening (AIMS) in parallel with iTRAQ-based quantitative proteomic analysis to highlight candidate proteins and validated their presence in pooled plasma-generated EVs from 30 healthy controls and 30 CRC patients. From these, we chose 14 potential EV-derived targets for further quantification by targeted MS assay in a separate individual cohort comprising of 73 CRC and 80 healthy subjects. 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Our results identify EV membrane proteins in common among CRC cell lines and altered plasma EV protein profiles in CRC patients and suggest plasma EV CD59 and TSPAN9 as a novel biomarker panel for detecting early-stage CRC.</description><subject>Antigens</subject><subject>Bioinformatics</subject><subject>Biological markers</subject><subject>Biomarkers</subject><subject>Biopsy</subject><subject>Cancer</subject><subject>Candidates</subject><subject>CD59 antigen</subject><subject>Cell culture</subject><subject>Cell organelles</subject><subject>Chemotherapy</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Developing countries</subject><subject>Diagnosis</subject><subject>Epidermal growth factor</subject><subject>Health aspects</subject><subject>LDCs</subject><subject>Lymph nodes</subject><subject>Mass spectrometry</subject><subject>Mass spectroscopy</subject><subject>Medical prognosis</subject><subject>Medical research</subject><subject>Membrane proteins</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Methods</subject><subject>Mortality</subject><subject>Plasma</subject><subject>Prostate</subject><subject>Proteins</subject><subject>Proteomes</subject><subject>Proteomics</subject><subject>Scientific imaging</subject><subject>Surgery</subject><subject>Tumor cells</subject><subject>Ultracentrifugation</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkk1vFSEUhidGY5vatTtD4sbNbfmYAWZjUm_rR9JqE1u3hGEOVyoDV5i5sb_JPynTW2vbCAvg8Jw3vIdTVS8JPmCsxYdGBwMpkwYTTIR4Uu1SLOiC87Z-em-_U-3nfIXLYIwILp5XO4xzQomgu9Xvk19j0ga8n7xO6BtkZzygMxi6pAOg8xRHcGFerfMurJAOPbrQaQUj9OhM54y-rsGMKQ4wpmt0GTbgPFoeN-0WLVGd1zoUkRLJ6HPcgEfnXudBo3cuDjr9KC6QjQkdF1EzuhhQtGgZfUzlqIvajdMX1TOrfYb923Wvunx_crH8uDj98uHT8uh0YWopx4XpuKY1CGJsjY0gsse0aWQnWU1A6rrlEvOGt7bvLTekZhTXnTCWas1abizbq95udddTN0BvIBQLXq2TK2-9VlE79fAmuO9qFTeqlURKSovAm1uBFH9OkEc1uDzXuFQ0TllRwUkrBG9wQV8_Qq_ilEKxd0PhVlIi_1Er7UG5YOP8abOoOhJ1QwWjhBTq4D9UmT0MzsQA5QfhYcLhNsGkmHMCe-eRYDW3mHrUYiXj1f3S3PF_G4r9AfW7zsQ</recordid><startdate>20221228</startdate><enddate>20221228</enddate><creator>Dash, Srinivas</creator><creator>Wu, Chia-Chun</creator><creator>Wu, Chih-Ching</creator><creator>Chiang, Sum-Fu</creator><creator>Lu, Yu-Ting</creator><creator>Yeh, Chien-Yuh</creator><creator>You, Jeng-Fu</creator><creator>Chu, Lichieh Julie</creator><creator>Yeh, Ta-Sen</creator><creator>Yu, Jau-Song</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5962-6185</orcidid><orcidid>https://orcid.org/0000-0001-8753-0239</orcidid><orcidid>https://orcid.org/0000-0002-4295-983X</orcidid><orcidid>https://orcid.org/0000-0002-8488-9614</orcidid><orcidid>https://orcid.org/0000-0002-7264-9672</orcidid><orcidid>https://orcid.org/0000-0001-5748-1659</orcidid><orcidid>https://orcid.org/0000-0001-7684-1285</orcidid></search><sort><creationdate>20221228</creationdate><title>Extracellular Vesicle Membrane Protein Profiling and Targeted Mass Spectrometry Unveil CD59 and Tetraspanin 9 as Novel Plasma Biomarkers for Detection of Colorectal Cancer</title><author>Dash, Srinivas ; 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This study explores the potential usefulness of tumor cell-derived EV membrane proteins as plasma biomarkers for early detection of colorectal cancer (CRC). EVs were isolated from the culture supernatants of four CRC cell lines by ultracentrifugation, and their protein profiles were analyzed by LC-MS/MS. Bioinformatics analysis of identified proteins revealed 518 EV membrane proteins in common among at least three CRC cell lines. We next used accurate inclusion mass screening (AIMS) in parallel with iTRAQ-based quantitative proteomic analysis to highlight candidate proteins and validated their presence in pooled plasma-generated EVs from 30 healthy controls and 30 CRC patients. From these, we chose 14 potential EV-derived targets for further quantification by targeted MS assay in a separate individual cohort comprising of 73 CRC and 80 healthy subjects. Quantitative analyses revealed significant increases in ADAM10, CD59 and TSPAN9 levels (2.19- to 5.26-fold, p < 0.0001) in plasma EVs from CRC patients, with AUC values of 0.83, 0.95 and 0.87, respectively. Higher EV CD59 levels were significantly correlated with distant metastasis (p = 0.0475), and higher EV TSPAN9 levels were significantly associated with lymph node metastasis (p = 0.0011), distant metastasis at diagnosis (p = 0.0104) and higher TNM stage (p = 0.0065). A two-marker panel consisting of CD59 and TSPAN9 outperformed the conventional marker CEA in discriminating CRC and stage I/II CRC patients from healthy controls, with AUC values of 0.98 and 0.99, respectively. Our results identify EV membrane proteins in common among CRC cell lines and altered plasma EV protein profiles in CRC patients and suggest plasma EV CD59 and TSPAN9 as a novel biomarker panel for detecting early-stage CRC.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>36612172</pmid><doi>10.3390/cancers15010177</doi><orcidid>https://orcid.org/0000-0002-5962-6185</orcidid><orcidid>https://orcid.org/0000-0001-8753-0239</orcidid><orcidid>https://orcid.org/0000-0002-4295-983X</orcidid><orcidid>https://orcid.org/0000-0002-8488-9614</orcidid><orcidid>https://orcid.org/0000-0002-7264-9672</orcidid><orcidid>https://orcid.org/0000-0001-5748-1659</orcidid><orcidid>https://orcid.org/0000-0001-7684-1285</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancers, 2022-12, Vol.15 (1), p.177 |
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| subjects | Antigens Bioinformatics Biological markers Biomarkers Biopsy Cancer Candidates CD59 antigen Cell culture Cell organelles Chemotherapy Colorectal cancer Colorectal carcinoma Developing countries Diagnosis Epidermal growth factor Health aspects LDCs Lymph nodes Mass spectrometry Mass spectroscopy Medical prognosis Medical research Membrane proteins Metastases Metastasis Methods Mortality Plasma Prostate Proteins Proteomes Proteomics Scientific imaging Surgery Tumor cells Ultracentrifugation |
| title | Extracellular Vesicle Membrane Protein Profiling and Targeted Mass Spectrometry Unveil CD59 and Tetraspanin 9 as Novel Plasma Biomarkers for Detection of Colorectal Cancer |
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