Research Papers:

Circulating tumor cells, tumor-derived extracellular vesicles and plasma cytokeratins in castration-resistant prostate cancer patients

Afroditi Nanou _, Frank A.W. Coumans, Guus van Dalum, Leonie L. Zeune, David Dolling, Wendy Onstenk, Mateus Crespo, Mariane Sousa Fontes, Pasquale Rescigno, Gemma Fowler, Penny Flohr, Christoph Brune, Stefan Sleijfer, Johann S. de Bono and Leon W.M.M. Terstappen

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Oncotarget. 2018; 9:19283-19293. https://doi.org/10.18632/oncotarget.25019

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Afroditi Nanou1, Frank A.W. Coumans2, Guus van Dalum3, Leonie L. Zeune1,4, David Dolling6, Wendy Onstenk5, Mateus Crespo6, Mariane Sousa Fontes6,7, Pasquale Rescigno6,7, Gemma Fowler6, Penny Flohr6, Christoph Brune4, Stefan Sleijfer5, Johann S. de Bono6,7 and Leon W.M.M. Terstappen1

1Department of Medical Cell BioPhysics, MIRA Institute, University of Twente, Enschede, the Netherlands

2Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam, the Netherlands

3Department of General, Visceral and Pediatric Surgery, University Hospital and Medical Faculty of the Heinrich-Heine University, Düsseldorf, Germany

4Department of Applied Mathematics, MIRA Institute and Faculty of EEMCS, University of Twente, Enschede, the Netherlands

5Department of Medical Oncology, Erasmus MC – Cancer Institute, Rotterdam, The Netherlands

6Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom

7Prostate Cancer Targeted Therapies Group, The Royal Marsden NHS Foundation Trust, London, United Kingdom

Correspondence to:

Afroditi Nanou, email: [email protected]

Leon W.M.M. Terstappen, email: [email protected]

Keywords: circulating tumor cells (CTCs); tumor-derived Extracellular Vesicles (tdEVs); cytokeratin 18 (CK18); caspase-cleaved cytokeratin 18 (ccCK18); castration-resistant prostate cancer (CRPC)

Received: November 07, 2017     Accepted: March 17, 2018     Published: April 10, 2018


Purpose: The presence of Circulating Tumor Cells (CTCs) in Castration-Resistant Prostate Cancer (CRPC) patients is associated with poor prognosis. In this study, we evaluated the association of clinical outcome in 129 CRPC patients with CTCs, tumor-derived Extracellular Vesicles (tdEVs) and plasma levels of total (CK18) and caspase-cleaved cytokeratin 18 (ccCK18).

Experimental Design: CTCs and tdEVs were isolated with the CellSearch system and automatically enumerated. Cut-off values dichotomizing patients into favorable and unfavorable groups of overall survival were set on a retrospective data set of 84 patients and validated on a prospective data set of 45 patients. Plasma levels of CK18 and ccCK18 were assessed by ELISAs.

Results: CTCs, tdEVs and both cytokeratin plasma levels were significantly increased in CRPC patients compared to healthy donors (HDs). All biomarkers except for ccCK18 were prognostic showing a decreased median overall survival for the unfavorable groups of 9.2 vs 21.1, 8.1 vs 23.0 and 10.0 vs 21.5 months respectively. In multivariable Cox regression analysis, tdEVs remained significant.

Conclusions: Automated CTC and tdEV enumeration allows fast and reliable scoring eliminating inter- and intra- operator variability. tdEVs provide similar prognostic information to CTC counts.

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