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Updated: May 4, 2026
Flow Cytometry Analysis of Tissue Factor Expression in Human Platelets
Published on: November 22, 2024
P14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway
Abdessamad Zerrouqi1, Beata Pyrzynska, Daniel J Brat
1Authors' Affiliations: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery; Departments of Pathology and Laboratory Medicine and Hematology and Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia.
Abstract:
How necrotic areas develop in tumors is incompletely understood but can impact progression. Recent findings suggest that the formation of vascular microthrombi contributes to tumor necrosis, prompting investigation of coagulation cascades. Here, we report that loss of tumor suppressor P14ARF can contribute to activating the clotting cascade in glioblastoma. P14ARF transcriptionally upregulated TFPI2, a Kunitz-type serine protease in the tissue factor pathway that inhibits the initiation of thrombosis reactions. P14ARF activation in tumor cells delayed their ability to activate plasma clotting. Mechanistically, P14ARF activated the TFPI2 promoter in a p53-independent manner that relied upon c-JUN, SP1, and JNK activity. Taken together, our results identify the critical signaling pathways activated by P14ARF to prevent vascular microthrombosis triggered by glioma cells. Stimulation of this pathway might be used as a therapeutic strategy to reduce aggressive phenotypes associated with necrotic tumors, including glioblastoma.
Insights
Loss of tumor suppressor P14ARF activates the clotting cascade in glioblastoma, promoting tumor necrosis. P14ARF normally prevents thrombosis by upregulating TFPI2, a clotting inhibitor.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Tumor necrosis is linked to vascular microthrombi formation and coagulation activation.
- The role of tumor suppressors in regulating thrombosis remains incompletely understood.
Purpose of the Study:
- To investigate the role of P14ARF in regulating the coagulation cascade within glioblastoma.
- To identify the molecular mechanisms by which P14ARF influences thrombosis and tumor necrosis.
Main Methods:
- Analysis of P14ARF's effect on TFPI2 expression and promoter activity.
- Investigating the signaling pathways (p53, c-JUN, SP1, JNK) involved in P14ARF-mediated TFPI2 regulation.
- Assessing the impact of P14ARF on plasma clotting activation in glioblastoma cells.
Main Results:
- Loss of P14ARF in glioblastoma promotes activation of the clotting cascade.
- P14ARF transcriptionally upregulates TFPI2, a Kunitz-type serine protease that inhibits thrombosis.
- P14ARF-mediated TFPI2 activation occurs independently of p53, involving c-JUN, SP1, and JNK signaling.
Conclusions:
- P14ARF plays a critical role in preventing vascular microthrombosis initiated by glioma cells.
- Targeting the P14ARF-TFPI2 pathway may offer a therapeutic strategy against aggressive, necrotic glioblastoma.
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