Abstract:Previous studies have revealed that the processes of tumor angiogenesis, metastasis and invasiveness are highly dependent on components of the blood coagulation cascade. Tissue factor (TF) is one of the key proteins in coagulation. Cumulative evidence suggested that in addition to its role in coagulation, TF regulates intracellular signaling pathways that serve an important role in angiogenesis, tumor development and metastasis. In the present study, TF expression in neuroblastoma as well as its association wi… Show more
“…TF is the main promoter of blood coagulation and the regulator of cancer angiogenesis. According to the report, there was a significant association between TF expression and NB prognosis [31]. What is more, the situation of the balance of angiogenesis in neuroblastoma is complex, and a series of molecules related to angiogenesis are detected in neuroblastoma, such as vascular endothelial growth factor, IL-8, fibroblast growth factor 2 [32,33].…”
Purpose
D-dimer levels are associated with tumor progression and prognosis in various cancers. However, there are few research about the relationship between D-dimer and neuroblastoma (NB). This study assessed the relationships of D-dimer levels with clinical features and overall survival (OS) in patients with NB.
Methods
Information about the clinical features of 365 patients and the prognosis of 301 patients was collected. The relationship between D-dimer levels and clinical features or OS was analyzed. We constructed the risk score based on Cox regression analysis and verified the predictive efficacy of the model through ROC curve and calibration curve.
Results
The results showed that D-dimer levels were significantly increased in patients with nonmediastinal tumor, tumor larger than 10 cm, stage 3–4 disease, bone marrow metastasis, unfavorable histology, bone metastasis, NMYC amplification, and the high-risk group (all P < 0.05). The Kaplan–Meier survival analysis showed that there were significant differences in 3- and 5-year OS (87.4% vs. 32.3%, 79.3% vs. 32.3%, P < 0.0001) between the low D-dimer and high D-dimer groups. In the high-risk group, the OS of high D-dimer was significantly lower than that of low D-dimer (P < 0.0001). All cases were divided into the training cohort (N = 211) and the validation cohort (N = 90). Multivariate analysis further suggested that D-dimer level, bone metastasis, and NMYC status were independent prognostic factors for OS (all P < 0.05). Based on the above three factors, we constructed the risk score in the training cohort. Survival analysis showed that compared with the other groups, the group with 11 scores had the worst prognosis (3-year OS 0%, P < 0.0001). The time-dependent ROC analysis and calibration curve indicated that the risk score had good accuracy.
Conclusions
Patients with high D-dimer levels tended to have unfavorable clinical characteristics and poor prognosis.
“…TF is the main promoter of blood coagulation and the regulator of cancer angiogenesis. According to the report, there was a significant association between TF expression and NB prognosis [31]. What is more, the situation of the balance of angiogenesis in neuroblastoma is complex, and a series of molecules related to angiogenesis are detected in neuroblastoma, such as vascular endothelial growth factor, IL-8, fibroblast growth factor 2 [32,33].…”
Purpose
D-dimer levels are associated with tumor progression and prognosis in various cancers. However, there are few research about the relationship between D-dimer and neuroblastoma (NB). This study assessed the relationships of D-dimer levels with clinical features and overall survival (OS) in patients with NB.
Methods
Information about the clinical features of 365 patients and the prognosis of 301 patients was collected. The relationship between D-dimer levels and clinical features or OS was analyzed. We constructed the risk score based on Cox regression analysis and verified the predictive efficacy of the model through ROC curve and calibration curve.
Results
The results showed that D-dimer levels were significantly increased in patients with nonmediastinal tumor, tumor larger than 10 cm, stage 3–4 disease, bone marrow metastasis, unfavorable histology, bone metastasis, NMYC amplification, and the high-risk group (all P < 0.05). The Kaplan–Meier survival analysis showed that there were significant differences in 3- and 5-year OS (87.4% vs. 32.3%, 79.3% vs. 32.3%, P < 0.0001) between the low D-dimer and high D-dimer groups. In the high-risk group, the OS of high D-dimer was significantly lower than that of low D-dimer (P < 0.0001). All cases were divided into the training cohort (N = 211) and the validation cohort (N = 90). Multivariate analysis further suggested that D-dimer level, bone metastasis, and NMYC status were independent prognostic factors for OS (all P < 0.05). Based on the above three factors, we constructed the risk score in the training cohort. Survival analysis showed that compared with the other groups, the group with 11 scores had the worst prognosis (3-year OS 0%, P < 0.0001). The time-dependent ROC analysis and calibration curve indicated that the risk score had good accuracy.
Conclusions
Patients with high D-dimer levels tended to have unfavorable clinical characteristics and poor prognosis.
“…Loss of the tumor suppressor Pten or E-cadherin also leads to TF upregulation [ 109 – 111 ]. In neuroblastoma, MYCN amplification positively correlates with TF [ 112 ]. Fig.…”
Section: Regulation Of Tissue Factor Expressionmentioning
Tissue factor (TF) is the primary initiator of the coagulation cascade, though its effects extend well beyond hemostasis. When TF binds to Factor VII, the resulting TF:FVIIa complex can proteolytically cleave transmembrane G protein-coupled proteaseactivated receptors (PARs). In addition to activating PARs, TF:FVIIa complex can also activate receptor tyrosine kinases (RTKs) and integrins. These signaling pathways are utilized by tumors to increase cell proliferation, angiogenesis, metastasis, and cancer stem-like cell maintenance. Herein, we review in detail the regulation of TF expression, mechanisms of TF signaling, their pathological consequences, and how it is being targeted in experimental cancer therapeutics.
“…These various sources of TF expression are powerful triggers for thrombin generation. TF expression is associated with poor prognosis in several malignant tumors [ 7 , 13 , 14 ]. TF is a potential molecular target for cancer therapy and TF inhibitors have been shown to suppress tumor exacerbation in vivo [ 15 ].…”
Background
Coagulation and fibrinolysis are distinct processes that are highly correlated. Cells control coagulation and fibrinolysis by expression of tissue factor and urokinase-type plasminogen activator receptor on their surface. Tumor cells express these proteins, adjust their microenvironment and induce tumor exacerbation. We hypothesized that the expression of plasma markers for coagulation and fibrinolysis in patients with soft tissue sarcomas (STSs) was dependent on the level of tumor malignancy. To elucidate which markers are predictive of recurrence, metastasis and prognosis, coagulation or fibrinolysis, we analyzed the correlation between plasma levels of thrombin-antithrombin III complex (TAT), soluble fibrin (SF), plasmin-α2 plasmin inhibitor complex (PIC), D-dimer (DD) and clinical parameters in patients with STSs.
Methods
TAT, SF, PIC or DD were measured in pre-treatment blood samples from 64 patients with primary STSs and analyzed with clinicopathological parameters, and 5-year recurrence free survival (RFS), 5-year metastasis free survival (MFS) and 5-year overall survival (OS) were evaluated.
Results
The metastasis group had significantly higher DD (p = 0.0394), PIC (p = 0.00532) and SF (p = 0.00249) concentrations than the group without metastasis. The group that died of disease showed significantly higher DD (p = 0.00105), PIC (p = 0.000542), SF (p = 0.000126) and TAT (p = 0.0373) than surviving patients. By dividing the patients into low and high groups, the group with high DD, PIC, SF and TAT showed significantly lower 5-year MFS and 5-year OS than the corresponding low group. Furthermore, in multivariate COX proportional hazard analysis of continuous variables for 5-year MFS, only PIC was found to be a significant factor (HR: 2.14).
Conclusion
Fibrinolysis was better than coagulation at reflecting the disease condition of patients with STS. Notably, PIC levels ≥ 1.1 can not only predict the risk of metastasis and poor prognosis, but also increasing PIC levels correspond to further increases in risks of metastasis and poor prognosis.
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