Progress in research on the role of fibrinogen in lung cancer
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Abstract
Lung cancer is one of the most prevalent malignancies worldwide. Local recurrence and distant metastasis remain the major causes of treatment failure. It has been recognized that the process of tumor growth and metastasis involves multiple interactions between tumor and host. Various biomarkers have been used for predicting tumor recurrence, metastasis, and prognosis in patients with lung cancer. However, these biomarkers are still controversial and require further validation. The relationship between malignancy and coagulation system disorders has been explored for more than a century. Fibrinogen is the most abundant plasma coagulation factor synthesized mainly by hepatic cells. Increased plasma fibrinogen levels were observed in various carcinomas such as gastric cancer, colon cancer, and pancreatic cancer. Recent studies have also investigated the role of fibrinogen in patients with lung cancer. This review aimed to address the role of fibrinogen in lung cancer.
1 Introduction
Lung cancer is a leading cause of cancer death around the world. The 5-year survival rate is only 15%, although various therapies are adopted [1]. Local recurrence and distant metastasis are the main reasons for treatment failure. Numerous factors including carcinoembryonic antigen, neuron-specific enolase, cytokeratin-19 fragments (CYFRA 21-1), and D-dimer for early diagnosis of distant metastasis, tumor recurrence, and prognosis in patients with lung cancer have been intensively identified [2,3]. However, the majority of these conventional indicators are still unsatisfactory.
Tumor-induced coagulation system disorders are commonly implicated in patients with malignancies. Fibrinogen is an essential constituent of the coagulation system. It is mainly synthesized in the liver and released into the circulation in response to systemic inflammation and malignancy. An increasing body of evidence has indicated the association between fibrinogen and tumor clinical stage, angiogenesis, metastatic spread, and response to therapy in patients with cancer [4,5]. The clinical value of fibrinogen in patients with lung cancer has also been investigated previously. To further understand its role, we reviewed fibrinogen estimation in patients with lung cancer.
2 Fibrinogen expression in lung cancer
High levels of fibrinogen have been observed in patients with lung cancer (Table 1). Kim et al. [9] reported that serum fibrinogen levels were increased in about 55.2% of patients with advanced non-small cell lung cancer (NSCLC), and its concentration may be higher in patients with squamous cell carcinoma than in patients with adenocarcinoma (4.5 ± 0.13 g/L vs 3.6 ± 0.28 g/L, p = 0.008) [4]. Elevated serum fibrinogen concentration can change blood viscosity, rheology, and endothelial function, which may facilitate microthrombosis in the pulmonary capillaries and make patients vulnerable to inflammation and ischemia [10,11]. Therefore, detection of serum fibrinogen levels may reflect lung tissue destruction. As previously reported, mean plasma fibrinogen concentration was associated with the pathological T stage but not with the pathological N stage [4]. However, other investigators found that there were no statistically significant differences in fibrinogen levels according to the TNM stage [9].
The expression of fibrinogen in lung cancer
| Histology (n) | n | Parameters evaluated | Main outcome of the study | Ref. |
|---|---|---|---|---|
| AC (18), SQ (69), LCC (2), other NSCLC (3) | 93 | Fibrinogen | Elevated plasma fibrinogen level was positively correlated with increasing tumor size, advanced pathological T stage, and SCC. | [4] |
| NS | 55 | Fibrinogen and FDP | Serum fibrinogen and FDP levels were elevated in lung cancer patients with metastases. | [6] |
| AC (165), SQ (106), LCC (22), SCC (46) | 339 | Fibrinogen | Increased serum fibrinogen levels were associated with advanced SCC or LCC. | [7] |
| AC (114), SQ (61), other NSCLC (9) | 184 | Fibrinogen | High pre- and postoperative fibrinogen levels in patients with NSCLC were associated with lymph node involvement of the tumor and pathologic stages. | [8] |
AC, adenocarcinoma; FDP, fibrinogen degradation product; LCC, large cell carcinoma; n, number of specimens; NS, not specified; NSCLC, non-small cell lung cancer; SCC, small cell carcinoma; SQ, squamous cell lung cancer.
Guan et al. [12] explored the relationship between fibrinogen and epidermal growth factor receptor (EGFR) mutation status in patients with NSCLC; they found that plasma fibrinogen levels were distinctly higher in patients with wild-type EGFR gene than in patients with EGFR mutations (3.57 g/L vs 2.95 g/L, p < 0.001). This shows that fibrinogen may assist in predicting EGFR mutation status in patients with NSCLC. However, additional studies are required to fully illustrate the molecular mechanism between fibrinogen and EGFR gene mutation status.
3 Role of fibrinogen in tumor progression
Cancer-related coagulation disorders have been thought to be responsible for the tumor cell growth, invasion, and distant metastasis. Recently, a series of experiments have shown the significance of fibrinogen in the pathogenesis of the cancer process [13,14,15]. As tumor cells dissociate from the primary focus into the circulation, fibrinogen can serve as a scaffold to bind tumor cells and platelets [15], which in turn contributes to tumor cell adherence to the distant organ and promotes tumor angiogenesis. Furthermore, fibrinogen has been implicated in the formation of tumor stroma, which provides gas exchange and nutrient for rapidly proliferating tumor cells.
Palumbo et al. [16] demonstrated that the deficiency of fibrinogen strongly reduced the spontaneous metastatic potential through both hematogenous and lymphatic routes but has no influences on the time required for the formation of palpable tumors, angiogenesis, and overall tumor architecture. Similarly, Palumbo et al. [17] also found that fibrinogen deficiency dramatically reduced the incidence of pulmonary metastases in fibrinogen-deficient transgenic mice. However, additional experiments are required to fully illustrate the relationship between fibrinogen and tumor metastasis.
As an extracellular protein matrix, fibrinogen not only promotes the migration of tumor cells but also protects tumor cells from the innate immune surveillance systems [14]. Zheng et al. [18] reported that fibrinogen can protect tumor cells from natural killer (NK) cell-mediated cytotoxicity by accumulating and forming dense fibrin layers around tumor cells. Gropp et al. [6] also found that fibrinogen split products can suppress immune reactions. Therefore, we can make the treatment more effective for patients with cancer by reducing the activity of the coagulation system.
4 Fibrinogen and the prognosis of lung cancer
The potential predictive value of fibrinogen for prognosis in patients with lung cancer has been reported in the previous investigations (Table 2). A significant relationship between initial response to chemotherapy and decreased fibrinogen levels was found in patients with elevated plasma levels of fibrinogen [5]. Jones et al. [4] reported that high fibrinogen values (plasma fibrinogen >5 g/L) were related to incomplete resection in patients with NSCLC. A retrospective analysis explored the correlation between preoperative serum fibrinogen levels and postoperative pulmonary complications (PPCs) in patients who underwent lung cancer resection. They found that high levels of preoperative serum fibrinogen (>400 mg/dL) were associated with the increased risk of PPCs, and it was an independent predictor regardless of sex and smoking status [30]. Jiang et al. [8] evaluated the value of pre- and postoperative plasma fibrinogen levels in predicting tumor recurrence and metastasis in 184 patients with I–IIIA NSCLC, who underwent radical surgery. They found a correlation between high pre- and postoperative plasma fibrinogen levels and tumor recurrence. This indicated that plasma fibrinogen levels may be used to predict tumor metastasis and recurrence for lung cancer patients who underwent surgery.
Fibrinogen and the prognosis of lung cancer
| Parameters evaluated | Main outcome of the study | Ref. |
|---|---|---|
| Fibrinogen | High fibrinogen values were associated with incomplete resection in NSCLC. | [4] |
| Fibrinogen | The reduction of plasma fibrinogen levels can evaluate the efficacy of chemotherapy in advanced NSCLC. | [5] |
| Fibrinogen | Pre- and postoperative plasma fibrinogen levels can predict tumor recurrence and metastasis for patients with NSCLC. | [8] |
| Fibrinogen | High fibrinogen levels were associated with poor prognosis in patients with advanced NSCLC. | [9] |
| Fibrinogen | Preoperative serum fibrinogen level was an independent prognostic marker in patients with operable NSCLC. | [19] |
| Fibrinogen | High plasma fibrinogen concentration indicated poor prognosis for NSCLC patients with brain metastases. | [20] |
| Fibrinogen | Plasma fibrinogen can predict the chemotherapy efficacy for patients with SCLC. | [21] |
| Fibrinogen, NLR | Plasma fibrinogen and NLR may predict the prognosis of patients with resectable NSCLC. | [22] |
| FA score | The FA score may be a promising prognostic predictor in patients with NSCLC. | [23] |
| AFR | High pre-resection AFR was associated with longer OS and disease-free survival (DFS) of patients with NSCLC. | [24] |
| Fibrinogen, AFR | AFR and fibrinogen were promising biomarkers to predict the clinical outcome of patients with NSCLC. | [25] |
| Fibrinogen, NLR | Combined fibrinogen and NLR can be used to predict prognosis for patients with resectable early-stage NSCLC. | [26] |
| AFR | Pretreatment AFR can predict the survival of patients with advanced NSCLC, who underwent first-line platinum-based chemotherapy. | [27] |
| Fibrinogen | Fibrinogen levels may influence the PFS of patients with NSCLC. | [28] |
| Fibrinogen, NLR | Combination of fibrinogen and NLR can predict tumor progression and the postoperative survival of patients with NSCLC. | [29] |
AFR, albumin/fibrinogen ratio; FA score, fibrinogen and serum albumin levels; NLR, neutrophil-to-lymphocyte ratio; NSCLC, non–small cell lung cancer; SCLC, small cell lung cancer.
Several investigators reported that patients with higher plasma fibrinogen levels tend to have poor progression-free survival (PFS) and overall survival (OS) [19,21]. A meta-analysis suggested that the level of plasma fibrinogen ≥400 mg/dL could be a promising indicator for worse OS in patients with lung cancer [31]. Ying et al. [27] explored the usefulness of the albumin-to-fibrinogen ratio (AFR) in patients with advanced NSCLC; they found that the PFS and OS in the high AFR group (>8.02) were markedly improved compared with those in the low AFR group. Therefore, fibrinogen may serve as a candidate biomarker for disease monitoring and prognostic evaluation in patients with lung cancer.
5 Fibrinogen and the treatment of lung cancer
It is increasingly recognized that the variation in fibrinogen concentration is associated with the treatment of malignancies. Zhu et al. [21] showed that fibrinogen levels decreased after one and two chemotherapy cycles in patients with small cell lung cancer (SCLC), and the degree of decline was associated with the treatment response. Morano et al. [32] also revealed that serum fibrinogen levels were significantly reduced after 4 weeks of pulmonary rehabilitation in patients with lung cancer.
Some investigators have focused on the therapeutic strategies for controlling tumor metastasis by improving the hypercoagulable status. As reported in the previous studies, the inhibition of tissue factor, factor Xa, and thrombin significantly reduced the experimental hematogenous metastasis [33]. Palumbo et al. [17] also found that thrombin inhibitor substantially diminished the metastatic potential of circulating tumor cells in fibrinogen-deficient mice but had no apparent influence on tumor cell proliferation in vitro. Therefore, anticoagulation therapy may prolong the survival time of patients with cancer.
6 Conclusion
The treatment and prognosis of cancer depend on the tumor stage, presence of comorbidities, and other factors. Various biomarkers and their combinations for tumor progression and prognosis have been explored. The coagulation abnormality in patients with cancer has been recognized for decades. Considerable attention has been paid to the relationship between the progression of lung cancer and fibrinogen. As we have mentioned above, fibrinogen is a valuable biomarker to predict tumor status, EGFR mutation status, and clinical outcome in patients with lung cancer and is associated with tumor progression and metastasis. As a noninvasive method, measurement of fibrinogen is simple, economical, and less traumatic in clinical practice. Further studies are needed to elucidate the relationship between fibrinogen and lung cancer biology.
Conflicts of interest: The authors state no conflict of interest.
References
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© 2020 Xing Liu and Bin Shi, published by De Gruyter
This work is licensed under the Creative Commons Attribution 4.0 International License.
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- Special Issue on Computing and Artificial Techniques for Life Science Applications - Part I
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- The impedance analysis of small intestine fusion by pulse source
- Errata
- Erratum to “Diagnostic performance of serum CK-MB, TNF-α and hs-CRP in children with viral myocarditis”
- Erratum to “MYL6B drives the capabilities of proliferation, invasion, and migration in rectal adenocarcinoma through the EMT process”
- Erratum to “Thermostable cellulase biosynthesis from Paenibacillus alvei and its utilization in lactic acid production by simultaneous saccharification and fermentation”
Articles in the same Issue
- Plant Sciences
- Dependence of the heterosis effect on genetic distance, determined using various molecular markers
- Plant Growth Promoting Rhizobacteria (PGPR) Regulated Phyto and Microbial Beneficial Protein Interactions
- Role of strigolactones: Signalling and crosstalk with other phytohormones
- An efficient protocol for regenerating shoots from paper mulberry (Broussonetia papyrifera) leaf explants
- Functional divergence and adaptive selection of KNOX gene family in plants
- In silico identification of Capsicum type III polyketide synthase genes and expression patterns in Capsicum annuum
- In vitro induction and characterisation of tetraploid drumstick tree (Moringa oleifera Lam.)
- CRISPR/Cas9 or prime editing? – It depends on…
- Study on the optimal antagonistic effect of a bacterial complex against Monilinia fructicola in peach
- Natural variation in stress response induced by low CO2 in Arabidopsis thaliana
- The complete mitogenome sequence of the coral lily (Lilium pumilum) and the Lanzhou lily (Lilium davidii) in China
- Ecology and Environmental Sciences
- Use of phosphatase and dehydrogenase activities in the assessment of calcium peroxide and citric acid effects in soil contaminated with petrol
- Analysis of ethanol dehydration using membrane separation processes
- Activity of Vip3Aa1 against Periplaneta americana
- Thermostable cellulase biosynthesis from Paenibacillus alvei and its utilization in lactic acid production by simultaneous saccharification and fermentation
- Spatiotemporal dynamics of terrestrial invertebrate assemblages in the riparian zone of the Wewe river, Ashanti region, Ghana
- Antifungal activity of selected volatile essential oils against Penicillium sp.
- Toxic effect of three imidazole ionic liquids on two terrestrial plants
- Biosurfactant production by a Bacillus megaterium strain
- Distribution and density of Lutraria rhynchaena Jonas, 1844 relate to sediment while reproduction shows multiple peaks per year in Cat Ba-Ha Long Bay, Vietnam
- Biomedical Sciences
- Treatment of Epilepsy Associated with Common Chromosomal Developmental Diseases
- A Mouse Model for Studying Stem Cell Effects on Regeneration of Hair Follicle Outer Root Sheaths
- Morphine modulates hippocampal neurogenesis and contextual memory extinction via miR-34c/Notch1 pathway in male ICR mice
- Composition, Anticholinesterase and Antipedicular Activities of Satureja capitata L. Volatile Oil
- Weight loss may be unrelated to dietary intake in the imiquimod-induced plaque psoriasis mice model
- Construction of recombinant lentiviral vector containing human stem cell leukemia gene and its expression in interstitial cells of cajal
- Knockdown of lncRNA KCNQ1OT1 inhibits glioma progression by regulating miR-338-3p/RRM2
- Protective effect of asiaticoside on radiation-induced proliferation inhibition and DNA damage of fibroblasts and mice death
- Prevalence of dyslipidemia in Tibetan monks from Gansu Province, Northwest China
- Sevoflurane inhibits proliferation, invasion, but enhances apoptosis of lung cancer cells by Wnt/β-catenin signaling via regulating lncRNA PCAT6/ miR-326 axis
- MiR-542-3p suppresses neuroblastoma cell proliferation and invasion by downregulation of KDM1A and ZNF346
- Calcium Phosphate Cement Causes Nucleus Pulposus Cell Degeneration Through the ERK Signaling Pathway
- Human Dental Pulp Stem Cells Exhibit Osteogenic Differentiation Potential
- MiR-489-3p inhibits cell proliferation, migration, and invasion, and induces apoptosis, by targeting the BDNF-mediated PI3K/AKT pathway in glioblastoma
- Long non-coding RNA TUG1 knockdown hinders the tumorigenesis of multiple myeloma by regulating the microRNA-34a-5p/NOTCH1 signaling pathway
- Large Brunner’s gland adenoma of the duodenum for almost 10 years
- Neurotrophin-3 accelerates reendothelialization through inducing EPC mobilization and homing
- Hepatoprotective effects of chamazulene against alcohol-induced liver damage by alleviation of oxidative stress in rat models
- FXYD6 overexpression in HBV-related hepatocellular carcinoma with cirrhosis
- Risk factors for elevated serum colorectal cancer markers in patients with type 2 diabetes mellitus
- Effect of hepatic sympathetic nerve removal on energy metabolism in an animal model of cognitive impairment and its relationship to Glut2 expression
- Progress in research on the role of fibrinogen in lung cancer
- Advanced glycation end product levels were correlated with inflammation and carotid atherosclerosis in type 2 diabetes patients
- MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB
- Knockdown of DDX46 inhibits trophoblast cell proliferation and migration through the PI3K/Akt/mTOR signaling pathway in preeclampsia
- Buformin suppresses osteosarcoma via targeting AMPK signaling pathway
- Effect of FibroScan test in antiviral therapy for HBV-infected patients with ALT <2 upper limit of normal
- LncRNA SNHG15 regulates osteosarcoma progression in vitro and in vivo via sponging miR-346 and regulating TRAF4 expression
- LINC00202 promotes retinoblastoma progression by regulating cell proliferation, apoptosis, and aerobic glycolysis through miR-204-5p/HMGCR axis
- Coexisting flavonoids and administration route effect on pharmacokinetics of Puerarin in MCAO rats
- GeneXpert Technology for the diagnosis of HIV-associated tuberculosis: Is scale-up worth it?
- Circ_001569 regulates FLOT2 expression to promote the proliferation, migration, invasion and EMT of osteosarcoma cells through sponging miR-185-5p
- Lnc-PICSAR contributes to cisplatin resistance by miR-485-5p/REV3L axis in cutaneous squamous cell carcinoma
- BRCA1 subcellular localization regulated by PI3K signaling pathway in triple-negative breast cancer MDA-MB-231 cells and hormone-sensitive T47D cells
- MYL6B drives the capabilities of proliferation, invasion, and migration in rectal adenocarcinoma through the EMT process
- Inhibition of lncRNA LINC00461/miR-216a/aquaporin 4 pathway suppresses cell proliferation, migration, invasion, and chemoresistance in glioma
- Upregulation of miR-150-5p alleviates LPS-induced inflammatory response and apoptosis of RAW264.7 macrophages by targeting Notch1
- Long non-coding RNA LINC00704 promotes cell proliferation, migration, and invasion in papillary thyroid carcinoma via miR-204-5p/HMGB1 axis
- Neuroanatomy of melanocortin-4 receptor pathway in the mouse brain
- Lipopolysaccharides promote pulmonary fibrosis in silicosis through the aggravation of apoptosis and inflammation in alveolar macrophages
- Influences of advanced glycosylation end products on the inner blood–retinal barrier in a co-culture cell model in vitro
- MiR-4328 inhibits proliferation, metastasis and induces apoptosis in keloid fibroblasts by targeting BCL2 expression
- Aberrant expression of microRNA-132-3p and microRNA-146a-5p in Parkinson’s disease patients
- Long non-coding RNA SNHG3 accelerates progression in glioma by modulating miR-384/HDGF axis
- Long non-coding RNA NEAT1 mediates MPTP/MPP+-induced apoptosis via regulating the miR-124/KLF4 axis in Parkinson’s disease
- PCR-detectable Candida DNA exists a short period in the blood of systemic candidiasis murine model
- CircHIPK3/miR-381-3p axis modulates proliferation, migration, and glycolysis of lung cancer cells by regulating the AKT/mTOR signaling pathway
- Reversine and herbal Xiang–Sha–Liu–Jun–Zi decoction ameliorate thioacetamide-induced hepatic injury by regulating the RelA/NF-κB/caspase signaling pathway
- Therapeutic effects of coronary granulocyte colony-stimulating factor on rats with chronic ischemic heart disease
- The effects of yam gruel on lowering fasted blood glucose in T2DM rats
- Circ_0084043 promotes cell proliferation and glycolysis but blocks cell apoptosis in melanoma via circ_0084043-miR-31-KLF3 axis
- CircSAMD4A contributes to cell doxorubicin resistance in osteosarcoma by regulating the miR-218-5p/KLF8 axis
- Relationship of FTO gene variations with NAFLD risk in Chinese men
- The prognostic and predictive value of platelet parameters in diabetic and nondiabetic patients with sudden sensorineural hearing loss
- LncRNA SNHG15 contributes to doxorubicin resistance of osteosarcoma cells through targeting the miR-381-3p/GFRA1 axis
- miR-339-3p regulated acute pancreatitis induced by caerulein through targeting TNF receptor-associated factor 3 in AR42J cells
- LncRNA RP1-85F18.6 affects osteoblast cells by regulating the cell cycle
- MiR-203-3p inhibits the oxidative stress, inflammatory responses and apoptosis of mice podocytes induced by high glucose through regulating Sema3A expression
- MiR-30c-5p/ROCK2 axis regulates cell proliferation, apoptosis and EMT via the PI3K/AKT signaling pathway in HG-induced HK-2 cells
- CTRP9 protects against MIA-induced inflammation and knee cartilage damage by deactivating the MAPK/NF-κB pathway in rats with osteoarthritis
- Relationship between hemodynamic parameters and portal venous pressure in cirrhosis patients with portal hypertension
- Long noncoding RNA FTX ameliorates hydrogen peroxide-induced cardiomyocyte injury by regulating the miR-150/KLF13 axis
- Ropivacaine inhibits proliferation, migration, and invasion while inducing apoptosis of glioma cells by regulating the SNHG16/miR-424-5p axis
- CD11b is involved in coxsackievirus B3-induced viral myocarditis in mice by inducing Th17 cells
- Decitabine shows anti-acute myeloid leukemia potential via regulating the miR-212-5p/CCNT2 axis
- Testosterone aggravates cerebral vascular injury by reducing plasma HDL levels
- Bioengineering and Biotechnology
- PL/Vancomycin/Nano-hydroxyapatite Sustained-release Material to Treat Infectious Bone Defect
- The thickness of surface grafting layer on bio-materials directly mediates the immuno-reacitivity of macrophages in vitro
- Silver nanoparticles: synthesis, characterisation and biomedical applications
- Food Science
- Bread making potential of Triticum aestivum and Triticum spelta species
- Modeling the effect of heat treatment on fatty acid composition in home-made olive oil preparations
- Effect of addition of dried potato pulp on selected quality characteristics of shortcrust pastry cookies
- Preparation of konjac oligoglucomannans with different molecular weights and their in vitro and in vivo antioxidant activities
- Animal Sciences
- Changes in the fecal microbiome of the Yangtze finless porpoise during a short-term therapeutic treatment
- Agriculture
- Influence of inoculation with Lactobacillus on fermentation, production of 1,2-propanediol and 1-propanol as well as Maize silage aerobic stability
- Application of extrusion-cooking technology in hatchery waste management
- In-field screening for host plant resistance to Delia radicum and Brevicoryne brassicae within selected rapeseed cultivars and new interspecific hybrids
- Studying of the promotion mechanism of Bacillus subtilis QM3 on wheat seed germination based on β-amylase
- Rapid visual detection of FecB gene expression in sheep
- Effects of Bacillus megaterium on growth performance, serum biochemical parameters, antioxidant capacity, and immune function in suckling calves
- Effects of center pivot sprinkler fertigation on the yield of continuously cropped soybean
- Special Issue On New Approach To Obtain Bioactive Compounds And New Metabolites From Agro-Industrial By-Products
- Technological and antioxidant properties of proteins obtained from waste potato juice
- The aspects of microbial biomass use in the utilization of selected waste from the agro-food industry
- Special Issue on Computing and Artificial Techniques for Life Science Applications - Part I
- Automatic detection and segmentation of adenomatous colorectal polyps during colonoscopy using Mask R-CNN
- The impedance analysis of small intestine fusion by pulse source
- Errata
- Erratum to “Diagnostic performance of serum CK-MB, TNF-α and hs-CRP in children with viral myocarditis”
- Erratum to “MYL6B drives the capabilities of proliferation, invasion, and migration in rectal adenocarcinoma through the EMT process”
- Erratum to “Thermostable cellulase biosynthesis from Paenibacillus alvei and its utilization in lactic acid production by simultaneous saccharification and fermentation”
