Tissue factor and PAR2 signaling in the tumor microenvironment

Area of Science:

• Oncology
• Hematology
• Molecular Biology

Background:

• Constitutive expression of tissue factor (TF) in cancer cells is linked to aggressive cancer phenotypes.
• TF-initiated coagulation cascade activation plays a critical role in cancer pathogenesis and metastasis.
• TF signaling shapes the tumor microenvironment and influences tumor cell migration.

Purpose of the Study:

• To elucidate the mechanisms by which TF-initiated signaling contributes to cancer progression.
• To explore the role of TF-VIIa-PAR2 and TF-VIIa-Xa signaling complexes in tumor cell migration and microenvironment modulation.
• To identify potential therapeutic targets within the TF-coagulation cascade signaling pathways for cancer treatment.

Main Methods:

• Utilized genetic mouse models to study TF's role in cancer.
• Investigated TF-VIIa binary complex-mediated activation of protease-activated receptor (PAR) 2.
• Examined PAR2 signaling pathways, including G protein-independent pathways via beta-arrestin scaffolding.
• Analyzed TF-VIIa-Xa signaling complex activation of PAR1 in metastatic contexts.

Main Results:

• TF-VIIa binding to PAR2 induces proangiogenic and immune-modulating cytokines, chemokines, and growth factors, shaping the tumor microenvironment.
• PAR2 activation by TF-VIIa promotes tumor cell migration through beta-arrestin scaffolding.
• Metastatic cells activate PAR1 via thrombin or the TF-VIIa-Xa complex in vascular and lymphatic systems.
• TF-VIIa-PAR2 signaling can be targeted for antiangiogenic therapy without increasing bleeding risk.

Conclusions:

• TF-initiated signaling is a crucial driver of cancer progression and metastasis.
• Targeting TF-VIIa-PAR2 interactions offers a potential antiangiogenic therapy with a favorable safety profile.
• Modulating coagulation and associated signaling pathways presents therapeutic opportunities for advanced and metastatic cancers.