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      Liquid biopsy in pancreatic ductal adenocarcinoma: current status of circulating tumor cells and circulating tumor DNA

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          Abstract

          Reliable biomarkers are required to evaluate and manage pancreatic ductal adenocarcinoma. Circulating tumor cells and circulating tumor DNA are shed into blood and can be relatively easily obtained from minimally invasive liquid biopsies for serial assays and characterization, thereby providing a unique potential for early diagnosis, forecasting disease prognosis, and monitoring of therapeutic response. In this review, we provide an overview of current technologies used to detect circulating tumor cells and circulating tumor DNA and describe recent advances regarding the multiple clinical applications of liquid biopsy in pancreatic ductal adenocarcinoma.

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          Identification of pancreatic cancer stem cells.

          Chenwei Li, David G Heidt, Piero Dalerba … (2007)
          Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.
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            Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases.

            W Jeffrey Allard, Jeri Matera, M. Craig Miller … (2004)
            The purpose of this study was to determine the accuracy, precision, and linearity of the CellSearch system and evaluate the number of circulating tumor cells (CTCs) per 7.5 mL of blood in healthy subjects, patients with nonmalignant diseases, and patients with a variety of metastatic carcinomas. The CellSearch system was used to enumerate CTCs in 7.5 mL of blood. Blood samples spiked with cells from tumor cell lines were used to establish analytical accuracy, reproducibility, and linearity. Prevalence of CTCs was determined in blood from 199 patients with nonmalignant diseases, 964 patients with metastatic carcinomas, and 145 healthy donors. Enumeration of spiked tumor cells was linear over the range of 5 to 1,142 cells, with an average recovery of >/=85% at each spike level. Only 1 of the 344 (0.3%) healthy and nonmalignant disease subjects had >/=2 CTCs per 7.5 mL of blood. In 2,183 blood samples from 964 metastatic carcinoma patients, CTCs ranged from 0 to 23,618 CTCs per 7.5 mL (mean, 60 +/- 693 CTCs per 7.5 mL), and 36% (781 of 2,183) of the specimens had >/=2 CTCs. Detection of >/=2 CTCs occurred at the following rates: 57% (107 of 188) of prostate cancers, 37% (489 of 1,316) of breast cancers, 37% (20 of 53) of ovarian cancers, 30% (99 of 333) of colorectal cancers, 20% (34 of 168) of lung cancers, and 26% (32 of 125) of other cancers. The CellSearch system can be standardized across multiple laboratories and may be used to determine the clinical utility of CTCs. CTCs are extremely rare in healthy subjects and patients with nonmalignant diseases but present in various metastatic carcinomas with a wide range of frequencies.
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              Detection and quantification of rare mutations with massively parallel sequencing.

              Isaac Kinde, Jian Wu, Nick Papadopoulos … (2011)
              The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Although massively parallel sequencing instruments are in principle well suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. The keys to this approach, called the Safe-Sequencing System ("Safe-SeqS"), are (i) assignment of a unique identifier (UID) to each template molecule, (ii) amplification of each uniquely tagged template molecule to create UID families, and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are considered mutant ("supermutants") only if ≥95% of them contain the identical mutation. We illustrate the utility of this approach for determining the fidelity of a polymerase, the accuracy of oligonucleotides synthesized in vitro, and the prevalence of mutations in the nuclear and mitochondrial genomes of normal cells.
              Article 0 comments Cited 452 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Stefanie S. Jeffrey:
                ORCID: https://orcid.org/0000-0003-4478-2764
                ssj@stanford.edu
                Journal
                Journal ID (nlm-ta): Mol Oncol
                Journal ID (iso-abbrev): Mol Oncol
                Journal ID (doi): 10.1002/(ISSN)1878-0261
                Journal ID (publisher-id): MOL2
                Title: Molecular Oncology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1574-7891
                ISSN (Electronic): 1878-0261
                Publication date (Electronic): 30 July 2019
                Publication date (Print): August 2019
                Volume: 13
                Issue: 8 ( doiID: 10.1002/mol2.v13.8 )
                Pages: 1623-1650
                Affiliations
                [ 1 ] Department of Laboratory Medicine Hallym University Sacred Heart Hospital Anyang Korea
                [ 2 ] Department of Laboratory Medicine Seoul National University College of Medicine Seoul Korea
                [ 3 ] Department of Laboratory Medicine Hallym University College of Medicine Anyang Korea
                [ 4 ] Department of Surgery Stanford University School of Medicine Stanford CA USA
                Author notes
                [*] [* ] Correspondence

                S. S. Jeffrey, MSLS P214, 1201 Welch Rd., Stanford, CA 94305‐5102, USA

                E‐mail: ssj@ 123456stanford.edu

                Author information
                https://orcid.org/0000-0003-4478-2764
                Article
                Publisher ID: MOL212537
                DOI: 10.1002/1878-0261.12537
                PMC ID: 6670020
                PubMed ID: 31243883
                SO-VID: 6ada65df-080d-42d0-a099-7f62aef2fbea
                Copyright © © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 18 October 2018
                Date revision received : 07 June 2019
                Date accepted : 25 June 2019
                Page count
                Figures: 1, Tables: 6, Pages: 28, Words: 20216
                Categories
                Subject: Review Article
                Subject: Review Article
                Custom metadata
                source-schema-version-number 2.0
                component-id mol212537
                cover-date August 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:01.08.2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: circulating tumor cells,circulating tumor dna,liquid biopsy,pancreatic cancer,pancreatic ductal adenocarcinoma,tumor‐derived circulating cell‐free dna
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: circulating tumor cells, circulating tumor dna, liquid biopsy, pancreatic cancer, pancreatic ductal adenocarcinoma, tumor‐derived circulating cell‐free dna

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