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      Pretreatment plasma fibrinogen level as a prognostic biomarker for patients with lung cancer

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          Abstract

          Many researchers have shown that pretreatment plasma fibrinogen levels are closely correlated with the prognosis of patients with lung cancer (LC). In this study, we thus performed a meta-analysis to systematically assess the prognostic value of pretreatment plasma fibrinogen levels in LC patients.

          A computerized systematic search in PubMed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) was performed up to March 15, 2018. Studies with available data on the prognostic value of plasma fibrinogen in LC patients were eligible for inclusion. The pooled hazard ratios (HRs) and odd ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the correlation between pretreatment plasma fibrinogen levels and prognosis as well as clinicopathological characteristics.

          A total of 17 studies with 6,460 LC patients were included in this meta-analysis. A higher pretreatment plasma fibrinogen level was significantly associated with worse overall survival (OS) (HR: 1.57; 95% CI: 1.39-1.77; p=0.001), disease-free survival (DFS) (HR: 1.53; 95% CI: 1.33-1.76; p=0.003), and progression-free survival (PFS) (HR: 3.14; 95% CI: 2.15-4.59; p<0.001). Furthermore, our subgroup and sensitivity analyses demonstrated that the pooled HR for OS was robust and reliable. In addition, we also found that a higher fibrinogen level predicted advanced TNM stage (III-IV) (OR=2.18, 95% CI: 1.79-2.66; p<0.001) and a higher incidence of lymph node metastasis (OR=1.74, 95% CI: 1.44-2.10; p=0.02).

          Our study suggested that higher pretreatment plasma fibrinogen levels predict worse prognoses in LC patients.

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          Most cited references24

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          Fibrinogen synthesized by cancer cells augments the proliferative effect of fibroblast growth factor-2 (FGF-2).

          Fibroblast growth factor (FGF)-2 is a critical growth factor in normal and malignant cell proliferation and tumor-associated angiogenesis. Fibrinogen and fibrin bind to FGF-2 and modulate FGF-2 functions. Furthermore, we have shown that extrahepatic epithelial cells are capable of endogenous production of fibrinogen. Herein we examined the role of fibrinogen and FGF-2 interactions on prostate and lung adenocarcinoma cell growth in vitro. Cell proliferation was measured by (3)H-thymidine uptake and the specificity of FGF-2-fibrinogen interactions was measured using wild-type and mutant FGF-2s, fibrinogen gamma-chain (FGG) RNAi and co-immunoprecipitation. Metabolic labeling, immunopurification and fluorography demonstrated de novo fibrinogen production. FGF-2 stimulated DU-145 cell proliferation, whereas neither FGF-2 nor fibrinogen affected the growth of PC-3 or A549 cells. Fibrinogen augmented the proliferative effect of FGF-2 on DU-145 cells. The role of fibrinogen in FGF-2-enhanced DNA synthesis was confirmed using an FGF-2 mutant that exhibits no binding affinity for fibrinogen. FGG transcripts were present in PC-3, A549 and DU-145 cells, but only PC-3 and A549 cells produced detectable levels of intact protein. RNAi-mediated knockdown of FGG expression resulted in decreased production of fibrinogen protein and inhibited (3)H-thymidine uptake in A549 and PC-3 cells by 60%, which was restored by exogenously added fibrinogen. FGF-2 and fibrinogen secreted by the cells were present in the medium as a soluble complex, as determined by coimmunoprecipitation studies. These data indicate that endogenously synthesized fibrinogen promotes the growth of lung and prostate cancer cells through interaction with FGF-2.
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            Coagulation facilitates tumor cell spreading in the pulmonary vasculature during early metastatic colony formation.

            Coagulation has long been known to facilitate metastasis. To pinpoint the steps where coagulation might play a role in the metastasis, we used three-dimensional visualization of direct infusion of fluorescence labeled antibody to observe the interaction of tumor cells with platelets and fibrinogen in isolated lung preparations. Tumor cells arrested in the pulmonary vasculature were associated with a clot composed of both platelets and fibrin(ogen). Initially, the cells attached to the pulmonary vessels were rounded. Over the next 2 to 6 hours, they spread on the vessel surface. The associated clot was lysed coincident with tumor cell spreading. To assess the importance of clot formation, we inhibited coagulation with hirudin, a potent inhibitor of thrombin. The number of tumor cells initially arrested in the lung of hirudin-treated mice was essentially the same as in control mice. However, tumor cell spreading and subsequent retention of the tumor cells in the lung was markedly inhibited in the anticoagulated mice. These associations of the tumor cells with platelets were independent of tumor cell expression of P-selectin ligands. This work identifies tumor cell spreading onto the vascular surface as an important component of the metastatic cascade and implicates coagulation in this process.
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              Serum fibrinogen is an independent prognostic factor in operable nonsmall cell lung cancer.

              Serum fibrinogen converted to insoluble fibrin by activated thrombin, plays an important role in the coagulation system. Increased fibrinogen considerably influences cancer cell growth, progression and metastasis. In nonsmall cell lung cancer (NSCLC), however, the association between serum fibrinogen concentration and prognosis has not been fully examined. We enlisted 567 operable NSCLC patients in our study. Preoperative serum fibrinogen was measured by the Clauss method. The association of serum fibrinogen concentration with clinical pathological factors and patient outcome was evaluated. Survival analysis indicated that serum fibrinogen was an independent prognostic factor in operable NSCLC. Patients with hyperfibrinogenemia had an elevated risk of disease progression and death compared to patients with normal fibrinogen levels. The hazard ratio was 1.49 (95% confidence interval [CI] 1.07-2.05) for disease progression and 1.64 (95% CI 1.06-2.53) for death. The trend linking increasing fibrinogen levels with risk was also statistically significant for both outcomes (p < 0.05). These analyses were adjusted for patient age, sex, smoking behavior, disease stage, tumor grade and histology. Kaplan-Meier survival curves showed similar results. Preoperative serum fibrinogen is a novel independent prognostic biomarker in operable NSCLC.
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                Author and article information

                Journal
                Clinics (Sao Paulo)
                Clinics (Sao Paulo)
                clin
                Clinics
                Faculdade de Medicina / USP
                1807-5932
                1980-5322
                18 February 2020
                2020
                : 75
                : e993
                Affiliations
                [I ]Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
                [II ]Department of Medical Ultrasound, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
                [III ]Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
                [IV ]Department of Medical Oncology, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou 510000, Guangdong, China.
                [V ]Breast Cancer Center, The Third Affiliated Hospital of Sun Yat-sen University, 600 Tianhe Road, Tianhe District, Guangzhou 510000, Guangdong, China
                Author notes

                #Authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-8042-7957
                https://orcid.org/0000-0001-9255-0023
                https://orcid.org/0000-0002-2796-7073
                https://orcid.org/0000-0002-5517-9541
                https://orcid.org/0000-0003-4951-577X
                https://orcid.org/0000-0002-3874-7332
                https://orcid.org/0000-0003-2781-6029
                https://orcid.org/0000-0003-0957-5794
                Article
                cln_75p1
                10.6061/clinics/2020/e993
                7026942
                32130355
                0ca75d4e-f3a2-41f3-9bba-91e80f03d296
                Copyright © 2020 CLINICS

                This is an Open Access article distributed under the terms of the Creative Commons License ( http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.

                History
                : 27 June 2019
                : 21 July 2019
                Categories
                Review Article

                Medicine
                pretreatment plasma fibrinogen,lung cancer,prognosis,meta-analysis
                Medicine
                pretreatment plasma fibrinogen, lung cancer, prognosis, meta-analysis

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