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Updated: May 30, 2026
Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
Tissue factor pathway inhibitor attenuates the progression of malignant pleural mesothelioma in nude mice
LaTerrica Williams1, Torry A Tucker, Kathy Koenig
1Texas Lung Injury Institute, University of Texas Health Science Center at Tyler, 11937 US Highway 271, Biomedical Research Building, Laboratory C-5, Tyler, TX 75708, USA.
Abstract:
Malignant pleural mesothelioma (MPM) is a rare cancer that is refractory to current treatments. It is characterized by a robust deposition of transitional fibrin that is in part promoted by tumor cells. MPM cells express tissue factor (TF) and the tissue factor pathway inhibitor (TFPI), but their contribution to the pathogenesis of MPM has been unclear. We found that REN MPM cells fail to express TFPI. Based on the tumor growth-promoting properties of TF, we hypothesized that the stable transfection of TFPI into REN MPM cells would decrease their aggressiveness. We tested our hypothesis using in vitro, in vivo, and ex vivo analyses. TFPI knock-in decreased the proliferation, invasion, and TF activity of REN cells in vitro. REN TFPI knock-in cells, empty vector, and naive control cells were next injected intrapleurally into nude mice. The expression of TFPI significantly decreased tissue invasion, inflammation, and the deposition of fibrin and collagen associated with tumor tissue, pleural effusions, and tumor burden. In ex vivo analyses, REN cells were cultured from harvested tumors. The overexpression of TFPI was maintained in cells propagated from TFPI knock-in tumors, and attenuated the activation of Factor X and the invasiveness of tumor cells. These analyses demonstrate that TFPI reduces the aggressiveness of MPM in vitro and in vivo, and that its effect involves the inhibition of TF procoagulant activity. These observations suggest that the interactions of TF and TFPI represent a novel therapeutic target in the treatment of MPM.
Insights
Tissue factor pathway inhibitor (TFPI) reduces malignant pleural mesothelioma (MPM) aggressiveness by inhibiting tissue factor (TF) activity. This finding suggests TFPI as a novel therapeutic target for treating this rare cancer.
Area of Science:
- Oncology
- Hematology
- Biochemistry
Background:
- Malignant pleural mesothelioma (MPM) is a rare and treatment-resistant cancer.
- MPM pathogenesis involves fibrin deposition, influenced by tumor cell-expressed tissue factor (TF) and tissue factor pathway inhibitor (TFPI).
- The role of TF and TFPI in MPM progression was previously unclear.
Purpose of the Study:
- To investigate the hypothesis that TFPI can decrease MPM aggressiveness.
- To evaluate the impact of TFPI reintroduction into TFPI-deficient MPM cells.
Main Methods:
- In vitro studies: TFPI knock-in into REN MPM cells to assess proliferation, invasion, and TF activity.
- In vivo studies: Intrapleural injection of TFPI-expressing and control MPM cells into nude mice to evaluate tumor burden, invasion, inflammation, and fibrin/collagen deposition.
- Ex vivo studies: Culturing cells from harvested tumors to confirm TFPI expression and assess Factor X activation and invasiveness.
Main Results:
- TFPI knock-in reduced REN MPM cell proliferation, invasion, and TF activity in vitro.
- In vivo, TFPI expression significantly decreased MPM-related tissue invasion, inflammation, fibrin, and collagen deposition.
- Ex vivo analysis confirmed sustained TFPI expression and its attenuation of Factor X activation and tumor cell invasiveness.
Conclusions:
- TFPI demonstrably reduces the aggressiveness of malignant pleural mesothelioma both in vitro and in vivo.
- The anti-cancer effects of TFPI are linked to the inhibition of TF procoagulant activity.
- Targeting the TF-TFPI interaction presents a promising novel therapeutic strategy for MPM treatment.
