Paraneoplastic autoimmune phenomena are found very commonly in prostate and ovarian carcinomas. They occur in the course of the evolvement of neoplasm and can regress with medicamentous or surgical treatment of the malignoma.

Hemostatic parameters have been investigated as molecular determinants of tumor progression. To analyze the dynamics of microparticle-associated tissue factor activity (MPTF), tissue factor antigen (TF-Ag), and angiopоietin-2 (ANG-2) in cancer patients before, during, and after active treatment and to explore their potential as biomarkers for metastatic occurrence and death. Blood for the analysis of MPTF, TF-Ag, ANG-2, and conventional hemostatic tests was sampled in 111 patients with various cancers at 4 consecutive visits: before first chemotherapy cycle, after 3 courses, at the sixth course, and 3 months after chemotherapy cessation. Patients were followed up until metastatic progression/death or the end of the study. MPTF did not change during chemotherapy, but increased significantly after treatment cessation. Total TF-Ag and ANG-2 decreased throughout active treatment. Significant drop of their levels was observed 3 months post therapy cessation. Progressive disease was significantly associated with higher pre-chemotherapy TF-Ag and fibrinogen. Elevated baseline levels of fibrinogen were associated with increased risk of shortened progression free survival. Cessation of chemotherapy is associated with significant change of hemostatic parameters. Pre-chemotherapy levels of TF-Ag and fibrinogen may be informative of disease state and prognosis.

Alteration of urokinase plasminogen activator receptor (uPAR) in neoplasms is a prerequisite for invasiveness and metastatic ability. In the present study, we aimed to evaluate the relationship of pre-chemotherapy soluble uPAR (suPAR) with the odds for metastasis, lack of disease control, and its predictive ability for progression-free survival (PFS). Baseline plasma suPAR levels were measured by ELISA in 89 patients with various cancers prior to initiation of systemic treatment. Patients were followed prospectively until metastatic progression or death. TCGA Pan-Cancer dataset was mined for available RNAseq expression data of the PLAUR gene in patients with breast, colon, and lung cancer, and therelevant genomic and clinical data were extracted for further analysis. Pre-chemotherapy suPAR levels were significantly associated with white blood cell counts and fibrinogen and were significantly elevated both in patients with metastatic disease and in patients with progression. Increasing suPAR was significantly associated with odds for progression in the prespecified multivariate analysis (odds ratio 2.47, 95% confidence interval 1.3 – 5.11). In univariate Cox regression, suPAR was predictive of shortened progression-free survival (PFS) (hazard ratio 1.065, 95% confidence interval 1.002 – 1.13; p = 0.041). There was a trend towards shortened PFS in patients with higher baseline suPAR levels (cutoff 8.1 ng/mL). In the TCGA lung cancer cohort, PLAUR mRNA expression was significantly associated with shortened PFS in both univariate and multivariate analyses. High PLAUR gene expression conferred significant survival disadvantage only in patients with colon and lung cancer. SuPAR may bear predictive potential for adverse outcomes in cancer, but its utility as a biomarker seems to be more pronounced in cancers with associated inflammatory state.

Malignancy arises and progresses in tight association with changes in the tumor microenvironment and deregulation of hemostatic system. Cancer induces hemostatic imbalance through production and secretion of procoagulant substances, suppression of anticoagulant mechanisms, endothelial activation, and angiogenic switch. Cancer cells are equipped with certain coagulation signaling receptors such as tissue factor TF and urokinase plasminogen activator receptor uPAR . Tissue factor as major initiator of coagulation, TF is considered the main cause for hypercoagulability in cancer. Constitutive TF expression by cancer cells is a hallmark of malignancy rendering tumors proangiogenic and prometastatic. TF fosters metastasis through coagulation-dependent pathways leading to fibrin deposition in the evolving premetastatic niche. TF has been identified as an independent predictor for metastatic development and adverse prognosis. uPAR Tissue overexpression of uPAR is demonstrated in almost all human cancers and is associated with advanced disease. Increased uPAR expression is driven by molecular events involving K-ras and SRC oncogenes. Transactivation of these receptors, mediated by binding to hemostatic proteins, activates intracellular signaling pathways, modulates gene expression and facilitates processes of tumor initiation, epithelial-to-mesenchymal transition, anoikis, and metastasis. By manipulating hemostatic processes, tumor induces tolerant host environment necessary for evasion of defense attacks, survival, and progression.

Based on observations of the link between hemostatic system and malignancy it is plausible to consider that plasma coagulation factors could serve as easily accessible markers for detection of malignant state and monitoring of cancer patients. Therefore, we hypothesized that tissue factor (TF), angiopoietin-2 (Ang-2) and soluble urokinase plasminogen activator receptor (suPAR) might perform as diagnostic and predictive biomarkers for the presence of malignancy as well as for the development of cancer-related events: metastatic progression and death. To analyze their performance TF-associated microparticle activity (MPTF), tissue factor antigen (TFAg), Ang-2 and suPAR were determined in 128 cancer patients with various cancer types receiving chemotherapy by sequential measurements (up to four times) at prespecified time points incorporated into interim and end-of-treatment analysis. MPTF activity was measured with Zymuphen MPTF kit, TFAg, suPAR and ANG-2 were quantitated by ELISA. Patients were followed up for progression free survival (PFS) from therapy initiation until occurrence of a combined event defined as either metastatic progression or death. In order to determine the predictive ability of hemostatic biomarkers for a PFS event Log-rank (Mantel-Cox) test was applied. ROC analysis was used to determine the cut off values for detection of an event, cut off values were transformed into binary variables and Kaplan-Meier curves were constructed. Cox regression analysis was applied to explore quantitatively the effect on the risk of progression. Results: Cut off values for the occurrence of an event were MPTF < 0.5 pg/ml (AUC 0.591), TFAg (√ pg/ml) > 8.28 (AUC 0.603), Ang-2 > 302.3 pg/ml (AUC 0.615) and suPAR (√ pg/ml) > 2.83. Shortened PFS was associated with decreased MPTF procoagulant activity and elevated plasma levels of TFAg, Ang-2, suPAR. As significant predictors for PFS were determined only TFAg (RR 4.57, p=0.038), Ang-2 (RR 2.138, p=0.031) and suPAR (RR 2.238, p=0.049). Conclusion: TFAg, Ang-2 and suPAR might be identified as significant adverse predictors of metastatic progression or death in cancer patients and risk is increased with elevated plasma levels. Disclosures No relevant conflicts of interest to declare.

No abstract

No abstract

No abstract