Abstract
Simple Summary“Liquid biopsy”, based on the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), provides non-invasive real-time monitoring of tumor evolution and therapeutic efficacy. We performed for the first time a direct comparison study on gene expression and DNA methylation markers in CTCs and paired plasma-derived exosomes and evaluated their prognostic significance in metastatic castration resistant prostate cancer. Our results revealed for the first time a significantly higher positivity of all markers in EpCAM-positive CTCs compared to plasma-derived exosomes. We report that in EpCAM-positive CTCs, CK-19, PSMA, TWIST1 expression and GSTP1 methylation are significantly correlated with worse overall survival (OS), while in exosomes, CK-8 expression and GSTP1 and RASSF1A methylation status were significantly correlated with a lower OS. We also enumerated CTC and tumor-derived extracellular vesicles (tdEVs) using CellSearch (CS) and found a correlation between the CTC and tumor-derived extracellular vesicles (tdEVs) enumeration values.Liquid biopsy, based on the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), provides non-invasive real-time monitoring of tumor evolution and therapeutic efficacy. We performed for the first time a direct comparison study on gene expression and DNA methylation markers in CTCs and paired plasma-derived exosomes and evaluated their prognostic significance in metastatic castration resistant prostate cancer. This prospective liquid biopsy (LB) study was based on a group of 62 metastatic castration resistant prostate cancer (mCRPC) patients and 10 healthy donors (HD) as controls. Identical blood draws were used to: (a) enumerate CTC and tumor-derived extracellular vesicles (tdEVs) using CellSearch (CS) and (b) analyze CTCs and paired plasma-derived exosomes at the gene expression and DNA methylation level. CTCs were enumerated using CellSearch in 57/62 patients, with values ranging from 5 to 854 cells/7.5 mL PB. Our results revealed for the first time a significantly higher positivity of gene expression markers (CK-8, CK-18, TWIST1, PSMA, AR-FL, AR-V7, AR-567 and PD-L1 mRNA) in EpCAM-positive CTCs compared to plasma-derived exosomes. GSTP1, RASSF1A and SCHLAFEN were methylated both in CTC and exosomes. In CTCs, Kaplan–Meier analysis revealed that CK-19 (p = 0.009), PSMA (p = 0.001), TWIST1 (p = 0.001) expression and GSTP1 (p = 0.001) methylation were correlated with OS, while in exosomes GSTP1 (p = 0.007) and RASSF1A (p = 0.001) methylation was correlated with OS. Our direct comparison study of CTCs and exosomes at gene expression and DNA methylation level, revealed for the first time a significantly higher positivity in EpCAM-positive CTCs compared to plasma-derived exosomes. Future perspective of this study should be the evaluation of clinical utility of molecular biomarkers in CTCs and exosomes on independent multicentric cohorts with mCRPC patients.
Highlights
Prostate cancer is the second most common cause of cancer-related death in men.Despite advances in screening, surgery, hormone therapy and chemotherapy, ~27,000 men still die in the USA each year from metastatic prostate cancer [1]
Our direct comparison study of circulating tumor cells (CTCs) and exosomes at gene expression and DNA methylation level, revealed for the first time a significantly higher positivity in EpCAM-positive CTCs compared to plasma-derived exosomes
Our results based on this prospective liquid biopsy study using identical blood draws clearly indicate a significantly higher positivity of gene expression and tumor DNA methylation markers in EpCAM-positive CTCs compared to plasma-derived exosomes
Summary
Prostate cancer is the second most common cause of cancer-related death in men. Despite advances in screening, surgery, hormone therapy and chemotherapy, ~27,000 men still die in the USA each year from metastatic prostate cancer [1]. CTCs are exceptionally heterogeneous, rare and show genetic differences from primary tumor cells. The unique biogenesis of exosomes, their ubiquitous production by all cell types, and their biological features in liquid biopsies have generated excitement for their potential as a source of cancer biomarkers [11]. Detection of DNA methylation-based markers on CTCs and exosomes can provide important information on epigenetic silencing of genes that play a critical role in the biology of metastasis [16]. In this study we performed for the first time a direct comparison study of gene expression (CK-19, CK-8, CK-18, TWIST1, ALDH1, PSMA, AR-FL, AR-V7, AR-567 and PD-L1) and DNA methylation (GSTP1 and RASSF1A) markers in CTCs and paired plasmaderived exosomes and evaluated their prognostic significance in metastatic castration resistant prostate cancer
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