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

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

doi:10.18632/oncotarget.25019

Abstract

PurposeThe 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 DesignCTCs 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.ResultsCTCs, 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.ConclusionsAutomated CTC and tdEV enumeration allows fast and reliable scoring eliminating inter- and intra- operator variability. tdEVs provide similar prognostic information to CTC counts.

Highlights

The presence of Circulating Tumor Cells (CTCs) in Castration-Resistant Prostate Cancer (CRPC) as detected by the CellSearch system is associated with poor outcome compared to patients without detectable CTCs [1,2,3,4,5,6]
We evaluated the association of clinical outcome in 129 CRPC patients with CTCs, tumor-derived Extracellular Vesicles and plasma levels of total (CK18) and caspase-cleaved cytokeratin 18
CTCs, tumor-derived Extracellular Vesicle (tdEV) and both cytokeratin plasma levels were significantly increased in CRPC patients compared to healthy donors (HDs)

Summary

Introduction

The presence of Circulating Tumor Cells (CTCs) in Castration-Resistant Prostate Cancer (CRPC) as detected by the CellSearch system is associated with poor outcome compared to patients without detectable CTCs [1,2,3,4,5,6]. We showed that the presence of small and large tumor microparticles with or without nucleus, positive for Epithelial Cell Adhesion Molecule (EpCAM) and Cytokeratin (CK) and negative for the leukocyte marker CD45 are associated with poor outcome in CRPC patients [7]. These tumor microparticles can be measured using the CellSearch system but do not meet the stringent criteria for CTCs. In the present study, we investigate the clinical relevance of both EpCAM+ CK+ CD45- tumor microparticles without a nucleus in blood, defined here as tumor-derived Extracellular Vesicles (tdEVs) and soluble cytokeratins in plasma of CRCP patients. The plasma samples of the two data sets were collected in a different way; different cut-off values for CK18 and ccCK18 were used for each one of them

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Conclusion