Abstract
The incidence of Merkel cell carcinoma (MCC), a rare and highly metastatic skin malignancy, has sharply increased in the last decade. Clinical biomarkers are urgently needed for MCC prognosis, treatment response monitoring, and early diagnosis of relapse. The clinical interest of circulating tumors cells (CTCs) has been validated in many solid cancers. The aim of this study was to compare CTC detection and characterization in blood samples of patients with MCC using the CellSearch System and the RosetteSep -DEPArray workflow, an innovative procedure to enrich, detect and isolate single CTCs. In preliminary experiments (using spiked MCC cell lines) both methods allowed detecting very few MCC cells. In blood samples from 19 patients with MCC at different stages, CellSearch detected MCC CTCs in 26% of patients, and the R-D workflow in 42% of patients. The detection of CTC-positive patients increased to 52% by the cumulative positivity rate of both methodologies. Moreover, Merkel cell polyomavirus DNA, involved in MCC oncogenesis, was detected in tumor biopsies, but not in all single CTCs from the same patient, reflecting the tumor heterogeneity. Our data demonstrate the possibility to detect, isolate and characterize CTCs in patients with MCC using two complementary approaches.
Highlights
Merkel Cell Carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, the incidence of which has been steadily increasing over the last decades[1,2]
We describe in this study two technologies for Circulating tumor cells (CTCs) detection in Merkel cell carcinoma (MCC) and Merkel cell polyomavirus (MCPyV) detection at single cell level in order to develop tools to better understand the biology of this cancer
To select markers that could be used to identify circulating MCC cells in blood samples, first we determined the phenotype of three MCC cell lines (MCCL-9, MCCL-11 and MKL-1) using markers that are commonly employed for the histopathological diagnosis of this cancer (Neuron-Specific Enolase (NSE); Synaptophysin, Chromogranin A; Cytokeratin 20 (CK20); and CD56) and markers usually used for CTCs detection (Epithelial Cell Adhesion Molecule (EpCAM); PanCK (8, 18, 19); Vimentin; CD24, CD44, CD45) (Fig. 1 and Supplementary Fig. S1)
Summary
Merkel Cell Carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, the incidence of which has been steadily increasing over the last decades[1,2]. The clonal integration of the viral DNA in the genome of MCC cells[7] suggests that this phenomenon is an early event occurring before malignant transformation[8] This virus is present in most MCC (about 80% of patients) and seems to play a direct role in malignant transformation, most notably through the intervention of oncogenic proteins[6]. One study correlated the presence of miR-375 in serum of patients with MCC23, some others determined T antigen antibodies as a prognostic marker in MCC24,25 and only three studies have investigated CTC detection in MCC: two based on EpCAM-positive selection of CTCs using the CellSearch system and one using the Maintrac system[26,27,28]. We describe in this study two technologies for CTC detection in MCC and MCPyV detection at single cell level in order to develop tools to better understand the biology of this cancer
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