The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity

C-Circles, self-primed telomeric C-strand templates for rolling circle amplification, are the only known alternative-lengthening-of-telomeres (ALT)-specific molecule. However, little is known about the biology of C-Circles and if they may be clinically useful. Here we show that C-Circles are secrete...

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Autores principales:	Yuan-Yin Chen, Rebecca Dagg, Yuchen Zhang, Joyce H. Y. Lee, Robert Lu, Nancy Martin La Rotta, Sandra Sampl, Medina Korkut-Demirbaş, Klaus Holzmann, Loretta M. S. Lau, Roger R. Reddel, Jeremy D. Henson
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	C-Circle Assay ALT telomere telomere maintenance mechanism exosomes cancer diagnostic Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2e1a777d525147f5857208e90642aece
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spelling	oai:doaj.org-article:2e1a777d525147f5857208e90642aece2021-11-11T15:29:22ZThe C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity10.3390/cancers132153692072-6694https://doaj.org/article/2e1a777d525147f5857208e90642aece2021-10-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5369https://doaj.org/toc/2072-6694C-Circles, self-primed telomeric C-strand templates for rolling circle amplification, are the only known alternative-lengthening-of-telomeres (ALT)-specific molecule. However, little is known about the biology of C-Circles and if they may be clinically useful. Here we show that C-Circles are secreted by ALT+ cancer cells inside exosomes, and that a blood-based C-Circle Assay (CCA) can provide an accurate diagnostic for ALT activity. Extracellular vesicles were isolated by differential centrifugation from the growth media of lung adenocarcinoma, glioblastoma, neuroblastoma, osteosarcoma, and soft tissue sarcoma cell lines, and C-Circles were detected in the exosome fraction from all eleven ALT+ cancer cell lines and not in any extracellular fraction from the eight matching telomerase positive cancer cell lines or the normal fibroblast strain. The existence of C-Circles in ALT+ exosomes was confirmed with exosomes isolated by iodixanol gradient separation and CD81-immunoprecipitation, and C-Circles in the exosomes were protected from nucleases. On average, 0.4% of the total ALT+ intracellular C-Circles were secreted in the exosomes every 24 h. Comparing the serum-based and tumor-based CCAs in 35 high risk neuroblastoma patients divided randomly into ALT+ threshold derivation and validation groups, we found the serum-based CCA to have 100% sensitivity (6/6), 70% specificity (7/10), and 81% concordance (13/16). We conclude that the secretion of C-Circles by ALT+ cancer cells in the exosomes provides a stable blood-based biomarker and a potential clinical diagnostic for ALT activity.Yuan-Yin ChenRebecca DaggYuchen ZhangJoyce H. Y. LeeRobert LuNancy Martin La RottaSandra SamplMedina Korkut-DemirbaşKlaus HolzmannLoretta M. S. LauRoger R. ReddelJeremy D. HensonMDPI AGarticleC-Circle AssayALTtelomeretelomere maintenance mechanismexosomescancer diagnosticNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5369, p 5369 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	C-Circle Assay ALT telomere telomere maintenance mechanism exosomes cancer diagnostic Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	C-Circle Assay ALT telomere telomere maintenance mechanism exosomes cancer diagnostic Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Yuan-Yin Chen Rebecca Dagg Yuchen Zhang Joyce H. Y. Lee Robert Lu Nancy Martin La Rotta Sandra Sampl Medina Korkut-Demirbaş Klaus Holzmann Loretta M. S. Lau Roger R. Reddel Jeremy D. Henson The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity
description	C-Circles, self-primed telomeric C-strand templates for rolling circle amplification, are the only known alternative-lengthening-of-telomeres (ALT)-specific molecule. However, little is known about the biology of C-Circles and if they may be clinically useful. Here we show that C-Circles are secreted by ALT+ cancer cells inside exosomes, and that a blood-based C-Circle Assay (CCA) can provide an accurate diagnostic for ALT activity. Extracellular vesicles were isolated by differential centrifugation from the growth media of lung adenocarcinoma, glioblastoma, neuroblastoma, osteosarcoma, and soft tissue sarcoma cell lines, and C-Circles were detected in the exosome fraction from all eleven ALT+ cancer cell lines and not in any extracellular fraction from the eight matching telomerase positive cancer cell lines or the normal fibroblast strain. The existence of C-Circles in ALT+ exosomes was confirmed with exosomes isolated by iodixanol gradient separation and CD81-immunoprecipitation, and C-Circles in the exosomes were protected from nucleases. On average, 0.4% of the total ALT+ intracellular C-Circles were secreted in the exosomes every 24 h. Comparing the serum-based and tumor-based CCAs in 35 high risk neuroblastoma patients divided randomly into ALT+ threshold derivation and validation groups, we found the serum-based CCA to have 100% sensitivity (6/6), 70% specificity (7/10), and 81% concordance (13/16). We conclude that the secretion of C-Circles by ALT+ cancer cells in the exosomes provides a stable blood-based biomarker and a potential clinical diagnostic for ALT activity.
format	article
author	Yuan-Yin Chen Rebecca Dagg Yuchen Zhang Joyce H. Y. Lee Robert Lu Nancy Martin La Rotta Sandra Sampl Medina Korkut-Demirbaş Klaus Holzmann Loretta M. S. Lau Roger R. Reddel Jeremy D. Henson
author_facet	Yuan-Yin Chen Rebecca Dagg Yuchen Zhang Joyce H. Y. Lee Robert Lu Nancy Martin La Rotta Sandra Sampl Medina Korkut-Demirbaş Klaus Holzmann Loretta M. S. Lau Roger R. Reddel Jeremy D. Henson
author_sort	Yuan-Yin Chen
title	The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity
title_short	The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity
title_full	The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity
title_fullStr	The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity
title_full_unstemmed	The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity
title_sort	c-circle biomarker is secreted by alternative-lengthening-of-telomeres positive cancer cells inside exosomes and provides a blood-based diagnostic for alt activity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/2e1a777d525147f5857208e90642aece
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The C-Circle Biomarker Is Secreted by Alternative-Lengthening-of-Telomeres Positive Cancer Cells inside Exosomes and Provides a Blood-Based Diagnostic for ALT Activity

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