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Cancers. 2021 Oct 26. pii: cancers13215369. doi: 10.3390/cancers13215369

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.

Chen YY¹, Dagg R², Zhang Y³, Lee JHY⁴, Lu R⁵, Martin La Rotta N⁶, Sampl S⁷, Korkut-Demirbaş M⁸, Holzmann K⁹, Lau LMS¹⁰, Reddel RR¹¹, Henson JD¹²

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¹Prince of Wales Clinical School, University of NSW, UNSW, Sydney 2052, Australia.
²Children's Cancer Research Unit, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Westmead 2145, Australia.
³Prince of Wales Clinical School, University of NSW, UNSW, Sydney 2052, Australia.
⁴Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia.
⁵Prince of Wales Clinical School, University of NSW, UNSW, Sydney 2052, Australia.
⁶Prince of Wales Clinical School, University of NSW, UNSW, Sydney 2052, Australia.
⁷Comprehensive Cancer Center, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
⁸Comprehensive Cancer Center, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
⁹Comprehensive Cancer Center, Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, 1090 Vienna, Austria.
¹⁰Children's Cancer Research Unit, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Westmead 2145, Australia.
¹¹Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia.
¹²Prince of Wales Clinical School, University of NSW, UNSW, Sydney 2052, Australia.

Abstract

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.

KEYWORDS: ALT, C-Circle Assay, cancer diagnostic, exosomes, telomere, telomere maintenance mechanism

Publikations ID: 34771533
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