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Role of tissue factor in the antitumor effect of recombinant human tumor necrosis factor-alpha in mice
F Nishigaki1, K Miyayasu, S Tsujimoto
1Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Abstract:
Recombinant tumor necrosis factor-alpha (rTNF-alpha) inhibited tumor growth of Meth A fibrosarcoma (Meth A) solid tumor in mice, and the antitumor effect of rTNF-alpha was significantly decreased by pretreatment with small doses or rTNF-alpha in mice. In in vitro experiments, incubation of human umbilical vein endothelial cells with rTNF-alpha enhanced procoagulant activity (PCA), which was drastically augmented after an addition of the conditioned medium of Meth A tumor cells. Furthermore, rTNF-alpha-induced PCA was decreased by pretreatment with rTNF-alpha in endothelial cells. This PCA was completely blocked after the addition of anti-human tissue factor (TF) murine monoclonal antibody. These results imply that in vivo antitumor effects of rTNF-alpha are mediated by expression of TF in endothelial cells, which is augmented by tumor released factor(s).
Insights
Recombinant tumor necrosis factor-alpha (rTNF-alpha) showed antitumor effects against Meth A fibrosarcoma. These effects are mediated by tissue factor (TF) expression on endothelial cells, influenced by tumor-secreted factors.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Recombinant tumor necrosis factor-alpha (rTNF-alpha) exhibits antitumor properties.
- The precise mechanisms underlying rTNF-alpha's in vivo efficacy require further elucidation.
Purpose of the Study:
- To investigate the role of endothelial cell procoagulant activity (PCA) in mediating the antitumor effects of rTNF-alpha.
- To identify factors contributing to rTNF-alpha-induced PCA in the context of Meth A fibrosarcoma.
Main Methods:
- In vivo studies using Meth A fibrosarcoma solid tumors in mice.
- In vitro experiments with human umbilical vein endothelial cells (HUVECs).
- Assays for procoagulant activity (PCA) and blockade with anti-human tissue factor (TF) antibodies.
Main Results:
- rTNF-alpha inhibited Meth A fibrosarcoma growth, an effect diminished by rTNF-alpha pretreatment.
- rTNF-alpha enhanced PCA in HUVECs, an effect amplified by Meth A tumor cell conditioned medium.
- rTNF-alpha-induced PCA was blocked by anti-TF antibodies, indicating TF's crucial role.
Conclusions:
- The in vivo antitumor effects of rTNF-alpha are mediated by TF expression on endothelial cells.
- Tumor-derived factors augment rTNF-alpha-induced TF expression and PCA.
- Targeting TF may enhance rTNF-alpha-based cancer therapies.