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A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma.
- Source :
-
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society [Liver Transpl] 2018 Jul; Vol. 24 (7), pp. 946-960. - Publication Year :
- 2018
-
Abstract
- Current clinicopathologic staging systems and serum biomarkers poorly discriminate tumor biology in hepatocellular carcinoma (HCC), with high recurrence rates following curative-intent surgical resection and liver transplantation (LT). Identification of accurate biomarkers for improved prognostication and treatment selection is a critical unmet need. We sought to develop a novel "liquid-biopsy" assay capable of detecting HCC circulating tumor cells (CTCs) and characterizing phenotypic subpopulations with prognostic significance. Using HCC cell lines, a tissue microarray, and human blood samples, an antibody cocktail targeting the cell-surface markers asialoglycoprotein receptor (ASGPR), glypican-3, and epithelial cell adhesion molecule was optimized for HCC CTC capture using the NanoVelcro CTC Assay. The ability of HCC CTCs and vimentin (VIM)-positive CTCs (a subpopulation expressing an epithelial-to-mesenchymal phenotype) to accurately discriminate tumor stage, recurrence, progression, and overall survival (OS) was evaluated in a prospective study of 80 patients. Multimarker capture detected greater numbers of CTCs than any individual antibody alone for both cell line and patient samples (P < 0.001). HCC CTCs were identified in 59/61 (97%) patients, and HCC (median, 6 CTCs) and non-HCC patients (median, 1 CTC; area under the receiver operating characteristic curve [AUROC] = 0.92; P < 0.001; sensitivity = 84.2%; specificity = 88.5%) were accurately discriminated. VIM-positive CTCs accurately discriminated early-stage, LT eligible patients (median, 0 CTCs) from locally advanced/metastatic, LT ineligible patients (median, 6 CTCs; AUROC = 0.89; P = 0.001; sensitivity = 87.1%; specificity = 90.0%), and predicted OS for all patients (hazard ratio [HR], 2.21; P = 0.001), and faster recurrence after curative-intent surgical or locoregional therapy in potentially curable early-stage HCC (HR, 3.14; P = 0.002). In conclusion, we developed a novel multimarker CTC enrichment assay that detects HCC CTCs with high efficiency and accuracy. A phenotypic subpopulation of VIM-positive CTCs appears to signify the presence of aggressive underlying disease and occult metastases and may have important implications for treatment selection. Liver Transplantation 24 946-960 2018 AASLD.<br /> (© 2018 by the American Association for the Study of Liver Diseases.)
- Subjects :
- Aged
Asialoglycoprotein Receptor analysis
Asialoglycoprotein Receptor metabolism
Biomarkers, Tumor metabolism
Carcinoma, Hepatocellular mortality
Carcinoma, Hepatocellular pathology
Cell Line, Tumor
Epithelial Cell Adhesion Molecule analysis
Epithelial Cell Adhesion Molecule metabolism
Female
Glypicans analysis
Glypicans metabolism
Healthy Volunteers
Humans
Immunoassay methods
Kaplan-Meier Estimate
Liquid Biopsy methods
Liver Cirrhosis blood
Liver Neoplasms mortality
Liver Neoplasms pathology
Male
Microfluidics methods
Middle Aged
Neoplasm Recurrence, Local mortality
Prognosis
Prospective Studies
Sensitivity and Specificity
Tissue Array Analysis
Vimentin metabolism
Biological Assay methods
Biomarkers, Tumor analysis
Carcinoma, Hepatocellular blood
Liver Neoplasms blood
Neoplasm Recurrence, Local diagnosis
Neoplastic Cells, Circulating metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1527-6473
- Volume :
- 24
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society
- Publication Type :
- Academic Journal
- Accession number :
- 29624843
- Full Text :
- https://doi.org/10.1002/lt.25062