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Regulation of tissue factor in NT2 germ cell tumor cells by cisplatin chemotherapy
Christine Jacobsen1, Karin Oechsle1, Jessica Hauschild1
1II. Medizinische Klinik und Poliklinik, Onkologisches Zentrum - Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
Background:
Patients with germ cell tumors (GCTs) receiving cisplatin-based chemotherapy are at increased risk of thrombosis, but the underlying cellular and molecular mechanisms remain obscure.
Objective:
To study baseline tissue factor (TF) expression by GCT cell lines and its modulation by cisplatin treatment.
Methods:
TF expression was assessed by single-stage clotting and thrombin generation assay, flow cytometry, ELISA, and Western blot analysis. Cell cycle analysis and detection of phosphatidylserine (PS) membrane exposure were carried out by flow cytometry. TF mRNA was analyzed by quantitative RT-PCR.
Results:
Significant expression of TF-specific procoagulant activity (PCA) was detected on three non-seminoma (NT2, 2102Ep, NCCIT) and one seminoma cell line (TCam-2). Treatment with 0.4μM cisplatin (corresponding to the IC50) for 48hrs increased TF PCA on NT2 cells 3-fold, an effect that was largely independent of PS exposure and that could not be explained by translocation of active TF from intracellular storage pools. Cisplatin-induced TF PCA expression in NT2 cells did not occur before 12hrs, but was steady thereafter and accompanied by a 2-fold increase in total and surface-located TF antigen. Importantly, increased TF gene transcription or production and release of an intermediate factor were not involved in this process. Cell cycle analysis suggested that cisplatin-induced G2/M arrest resulted in an accumulation of procoagulant TF on the membrane surface of NT2 cells.
Conclusions:
In addition to induction of apoptosis/necrosis with PS-mediated activation of preformed TF, cisplatin may alter the procoagulant phenotype of GCT cells through an increase in total cellular TF antigen.
Insights
Cisplatin chemotherapy increases tissue factor (TF) in germ cell tumors (GCTs), potentially explaining thrombosis risk. Cisplatin treatment elevates TF antigen on GCT cells, independent of apoptosis, suggesting a direct procoagulant effect.
Area of Science:
- Oncology
- Hematology
- Cell Biology
Background:
- Patients with germ cell tumors (GCTs) undergoing cisplatin chemotherapy face elevated thrombosis risks.
- The precise cellular and molecular mechanisms driving this increased risk remain unclear.
Purpose of the Study:
- To investigate baseline tissue factor (TF) expression in GCT cell lines.
- To determine how cisplatin treatment modulates TF expression in these cells.
Main Methods:
- Assessed TF expression using clotting assays, thrombin generation, flow cytometry, ELISA, and Western blot.
- Analyzed cell cycle and phosphatidylserine (PS) exposure via flow cytometry.
- Quantified TF mRNA using RT-PCR.
Main Results:
- Significant TF procoagulant activity (PCA) was found on multiple GCT cell lines.
- Cisplatin treatment (IC50) increased TF PCA on NT2 cells by 3-fold within 48 hours.
- This increase was linked to elevated TF antigen and G2/M cell cycle arrest, not primarily PS exposure or de novo synthesis.
Conclusions:
- Cisplatin may enhance GCT cell procoagulant activity by increasing total TF antigen.
- This TF modulation, beyond apoptosis-induced TF activation, contributes to thrombosis risk in GCT patients.
