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      D-dimer is an essential accompaniment of circulating tumor cells in gastric cancer

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          Abstract

          Background

          Fibrinogen (FIB) is an important source of fibrin, which plays a crucial role in circulating tumor cells (CTCs) extravasation and distant metastasis development. We hypothesize it’s stable final product, plasma D-dimer, may be associated with CTCs appearance and can reflect the metastatic phenotype in cancer patients.

          Methods

          We first verified our hypothesis in different murine gastric cancer metastasis models in vivo, plasma D-dimer and fibrinogen as well as its degradation products were directly examined in three metastasis immune-deficient mouse models and in controls. Next, we gathered and analyzed the result of plasma D-dimer levels and CTCs numbers in 41 advanced primary gastric cancer (GC) patients. A follow-up study was conducted in these patients.

          Results

          In three in vivo murine metastasis models, plasma D-dimer levels were extremely elevated in a hematogenous and intraperitoneal murine model of metastasis compared with a subcutaneous tumor model and the control group, supporting our previous hypothesis. While in 41 GC patients, the result displayed that plasma D-dimer levels were remarkably increased in patients with distant metastases, especially in visceral metastases patients. Additionally, linear association was shown between D-dimer level and CTCs numbers ( R 2 = 0.688, p < 0.001), additionally, plasma D-dimer represent a better survival predictor than CTCs.

          Conclusions

          Plasma D-dimer is an essential accompaniment of CTCs in GC that is easy to measure and lower in cost, and can be used in the detection of hematogenous metastasis.

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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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            High D-dimer levels are associated with poor prognosis in cancer patients.

            Peter Quehenberger, Christoph Zielinski, Oswald Wagner … (2012)
            Systemic activation of hemostasis is frequently observed in cancer patients, even in the absence of thrombosis. Moreover, this activation has been implicated in tumor progression, angiogenesis and metastatic spread. Increased levels of D-dimer, which is a degradation product of cross-linked fibrin, indicate a global activation of hemostasis and fibrinolysis. In a prospective and observational cohort study, we assessed the prognostic value of D-dimer levels for overall survival and mortality risk in 1178 cancer patients included in the Vienna Cancer and Thrombosis Study (CATS). Patients were followed over 2 years at regular intervals until occurrence of symptomatic venous thromboembolism or death. D-dimer levels were measured with a quantitative D-dimer latex agglutination assay The main solid tumors were malignancies of the lung (n=182), breast (n=157), lower gastrointestinal tract (n=133), pancreas (n=74), stomach (n=50), kidney (n=37), prostate (n=133), and brain (n=148); 201 of the patients had hematologic malignancies; 63 had other tumors. During a median follow-up of 731 days, 460 (39.0%) patients died. The overall survival probabilities for patients with D-dimer levels categorized into four groups based on the 1(st), 2(nd) and 3(rd) quartiles of the D-dimer distribution in the total study population were 88%, 82%, 66% and 53% after 1 year, and 78%, 66%, 50% and 30% after 2 years, respectively (P<0.001). The univariate hazard ratio of D-dimer (per double increase) for mortality was 1.5 (95% confidence interval: 1.4-1.6, P<0.001) and remained increased in multivariable analysis including tumor subgroups, age, sex and venous thromboembolism. High D-dimer levels were associated with poor overall survival and increased mortality risk in cancer patients.
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              The relationship between tissue factor and cancer progression: insights from bench and bedside.

              W. Van Den Wollenberg, Pieter Reitsma, Henri Versteeg … (2012)
              It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TF-dependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF.
              Article 0 comments Cited 113 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Dongmei Diao: diaomei310@163.com
                Yao Cheng: chengyao832@aliyun.com
                Yongchun Song: dr.syc@163.com
                Hao Zhang: dr.healthzhang@gmail.com
                Zhangjian Zhou: zhouzhangjian1989@yahoo.com
                Chengxue Dang: 86-29-85324612 , dangchengxue@mail.xjtu.edu.cn
                Journal
                Journal ID (nlm-ta): BMC Cancer
                Journal ID (iso-abbrev): BMC Cancer
                Title: BMC Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2407
                Publication date (Electronic): 13 January 2017
                Publication date PMC-release: 13 January 2017
                Publication date Collection: 2017
                Volume: 17
                Electronic Location Identifier: 56
                Affiliations
                [1 ]Oncology Surgery Department, First Affiliated Hospital of Xi’an Jiaotong University, 277 West Yanta Road, Xi’an, Shaanxi 710061 People’s Republic of China
                [2 ]Thoracic Surgery Department, Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, People’s Republic of China
                Article
                Publisher ID: 3043
                DOI: 10.1186/s12885-016-3043-1
                PMC ID: 5237231
                PubMed ID: 28086824
                SO-VID: 2a1674cc-9e55-4c31-b7a8-b6c08ffae76e
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 18 June 2016
                Date accepted : 28 December 2016
                Funding
                Funded by: National Natural Scientific Foundation of China
                Award ID: 81501826
                Award Recipient :
                Funded by: Science and Technology research and development program of Shaanxi Province
                Award ID: 2016SF-184
                Award Recipient :
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: d-dimer,gastric cancer (gc),metastasis,circulating tumor cells (ctcs),outcome
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: d-dimer, gastric cancer (gc), metastasis, circulating tumor cells (ctcs), outcome

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