Individual Profiling of Circulating Tumor Cell Composition and Therapeutic Outcome in Patients with Hepatocellular Carcinoma

Nel, Ivonne; Baba, Hideo A.; Ertle, Judith; Weber, Frank; Sitek, Barbara; Eisenacher, Martin; Meyer, Helmut E.; Schlaak, Joerg F.; Hoffmann, Andreas-Claudius

doi:10.1593/tlo.13271

Cited by 52 publications

(31 citation statements)

References 28 publications

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“…In another study, CTCs were found in 28% of HCC patient samples analysed with the CellSearch system but in 100% of samples analysed with an EpCAM-independent filtration method. 43 In a third study, multiimmunofluorescence identified considerable heterogeneity within CTC populations in HCC patients 44 and changes in the ratio of epithelial to mesenchymal cells were associated with a longer time to disease progression.…”

Section: Tumor Markers and Signaturesmentioning

confidence: 97%

High‐resolution imaging for the detection and characterisation of circulating tumour cells from patients with oesophageal, hepatocellular, thyroid and ovarian cancers

et al. 2015

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Interest has increased in the potential role of circulating tumour cells in cancer management. Most cell‐based studies have been designed to determine the number of circulating tumour cells in a given volume of blood. Ability to understand the biology of the cancer cells would increase the clinical potential. The purpose of this study was to develop and validate a novel, widely applicable method for detection and characterisation of circulating tumour cells. Cells were imaged with an ImageStreamX imaging flow cytometer which allows detection of expression of multiple biomarkers on each cell and produces high‐resolution images. Depletion of haematopoietic cells was by red cell lysis, leukocyte common antigen CD45 depletion and differential centrifugation. Expression of epithelial cell adhesion molecule, cytokeratins, tumour‐type‐specific biomarkers and CD45 was detected by immunofluorescence. Nuclei were identified with DAPI or DRAQ5 and brightfield images of cells were collected. The method is notable for the dearth of cell damage, recoveries greater than 50%, speed and absence of reliance on the expression of a single biomarker by the tumour cells. The high‐quality images obtained ensure confidence in the specificity of the method. Validation of the methodology on samples from patients with oesophageal, hepatocellular, thyroid and ovarian cancers confirms its utility and specificity. Importantly, this adaptable method is applicable to all tumour types including those of nonepithelial origin. The ability to measure simultaneously the expression of multiple biomarkers will facilitate analysis of the cancer cell biology of individual circulating tumour cells.

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Section: Tumor Markers and Signaturesmentioning

confidence: 97%

High‐resolution imaging for the detection and characterisation of circulating tumour cells from patients with oesophageal, hepatocellular, thyroid and ovarian cancers

et al. 2015

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“…Because only 20%‐35% of HCCs express EpCAM, methods based on EpCAM alone have resulted in low CTC detection rates and limited utility for HCC . Alternative CTC capture methods using antibodies directed at hepatocyte‐specific cell surface markers, CD45 depletion, or microfluidic systems have all demonstrated increased efficiency in isolating HCC CTCs. Furthermore, these non‐EpCAM–based methods allow for the capture of distinct CTC subpopulations with more mesenchymal properties in HCC …”

mentioning

confidence: 99%

A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma

et al. 2018

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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.

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“…Numerous devices were developed on the basis of this characteristics and collect cells with larger size (often >15 μm), including dielectrophoresis (DEP) [43,44], optically induced dielectrophorestic (ODEP) [45] force-dependent devices, and filter-based systems [46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61]. However, other investigators found that the size of real CTCs could be greatly differed from cell lines [62], and might even vary interindividually and intraindividually [63,64]. The size criteria of CTC definition remain in debate.…”

Section: Natures Of Ctcsmentioning

confidence: 99%

The Selection Strategy for Circulating Tumor Cells (CTCs) Isolation and Enumeration: Technical Features, Methods, and Clinical Applications

Hsieh¹,

Wu²

2016

Tumor Metastasis

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The key aim of the proposed chapter is to provide readers a brief description for the most important parts of the field of circulating tumor cells (CTCs): the core techniques, including negative and positive selection-based CTC isolation, and the differences between them. Most importantly, we will also review the clinical applications and important findings in clinical trials. The evidence-based review will not only help clinicians use CTCs to predict recurrence and foresee the disease-related outcomes but also to inspire the researchers in this field to conduct further investigations.

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Individual Profiling of Circulating Tumor Cell Composition and Therapeutic Outcome in Patients with Hepatocellular Carcinoma

Cited by 52 publications

References 28 publications

High‐resolution imaging for the detection and characterisation of circulating tumour cells from patients with oesophageal, hepatocellular, thyroid and ovarian cancers

High‐resolution imaging for the detection and characterisation of circulating tumour cells from patients with oesophageal, hepatocellular, thyroid and ovarian cancers

A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma

The Selection Strategy for Circulating Tumor Cells (CTCs) Isolation and Enumeration: Technical Features, Methods, and Clinical Applications

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