Format

Send to

Choose Destination
J Extracell Vesicles. 2018 Aug 7;7(1):1505403. doi: 10.1080/20013078.2018.1505403. eCollection 2018.

Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma.

Vagner T1,2,3,4, Spinelli C1,2,3,4,5, Minciacchi VR1,2,3,4,6, Balaj L7, Zandian M1,2,3,4, Conley A2, Zijlstra A8, Freeman MR1,2,3,4,9, Demichelis F10, De S11, Posadas EM12, Tanaka H1,3,4, Di Vizio D1,2,3,4,9.

Author information

1
Department of Biomedical Sciences, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
2
Department of Pathology and Laboratory Medicine, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
3
Samuel Oschin Comprehensive Cancer Institute, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
4
Department of Surgery, Division of Cancer Biology and Therapeutics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
5
Department of Pediatrics, McGill University, The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
6
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany.
7
Department of Neurology, Program in Neuroscience, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
8
Dep nartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
9
Department of Medicine, University of California, Los Angeles, CA, USA.
10
Centre for Integrative Biology, University of Trento, Trento, Italy.
11
Department of Pathology and Laboratory Medicine, Rutgers Cancer Institute, Rutgers the State University of New Jersey, New Brunswick, NJ, USA.
12
Urologic Oncology Program and Uro-Oncology Research Laboratories, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Abstract

Cancer-derived extracellular vesicles (EVs) are membrane-enclosed structures of highly variable size. EVs contain a myriad of substances (proteins, lipid, RNA, DNA) that provide a reservoir of circulating molecules, thus offering a good source of biomarkers. We demonstrate here that large EVs (L-EV) (large oncosomes) isolated from prostate cancer (PCa) cells and patient plasma are an EV population that is enriched in chromosomal DNA, including large fragments up to 2 million base pair long. While L-EVs and small EVs (S-EV) (exosomes) isolated from the same cells contained similar amounts of protein, the DNA was more abundant in L-EV, despite S-EVs being more numerous. Consistent with in vitro observations, the abundance of DNA in L-EV obtained from PCa patient plasma was variable but frequently high. Conversely, negligible amounts of DNA were present in the S-EVs from the same patients. Controlled experimental conditions, with spike-ins of L-EVs and S-EVs from cancer cells in human plasma from healthy subjects, showed that circulating DNA is almost exclusively enclosed in L-EVs. Whole genome sequencing revealed that the DNA in L-EVs reflects genetic aberrations of the cell of origin, including copy number variations of genes frequently altered in metastatic PCa (i.e. MYC, AKT1, PTK2, KLF10 and PTEN). These results demonstrate that L-EV-derived DNA reflects the genomic make-up of the tumour of origin. They also support the conclusion that L-EVs are the fraction of plasma EVs with DNA content that should be interrogated for tumour-derived genomic alterations.

KEYWORDS:

DNA; L-EVs; S-EVs; liquid biopsy; plasma; prostate cancer

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center