Selective induction of endothelial cell tissue factor in the presence of a tumour-derived mediator: A potential mechanism of flavone acetic acid action in tumour vasculature
✍ Scribed by J. Clifford Murray; Matthias Clauss; Juliana Denekamp; David Stern
- Publisher
- John Wiley and Sons
- Year
- 1991
- Tongue
- French
- Weight
- 747 KB
- Volume
- 49
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Flavone acetic acid (FAA) is a potentially useful antitumour agent which has been reported to induce changes in tumour vasculature, in particular loss of bloodflow. This led us to examine whether endothelium could be a cellular target of FAA action, with resultant modulation of cell-surface coagulant properties leading to activation of coagulation and block- ade of tumour blood flow. Incubation of endothelium with FAA led to the expression of functional tissue factor on the cell surface, in a time-dependent and dose-dependent (halfmaximal at 0.60.7 mg/ml) manner. Induction of tissue-factor activity resulted from de novo translation of the tissue factor message. To explain the selectivity of FAA's action on tumour vasculature in vivo, we considered i t s interaction with tumour-derived factors. Starting w i t h serum-free FO-Imelanoma cell-conditioned medium, a co-factor enhancing FAA-mediated induction of endothelial tissue factor (FO-I factor) was partially purified by sequential ion exchange and reverse phase chromatography, followed by preparative SDS-PAGE. The FO-I factor migrates with an apparent Mr of approx. 20 to 25,000 on non-reduced SDS-PAGE, is sensitive to protease K, and augments the effect of FAA on endothelialcell-tissue factor. This activity is not found in supernatants from non-neoplastically transformed cell lines. These data lead us to hypothesize that FAA exerts i t s action, at least in part, by promoting activation of coagulation on the endothelial surface, and this effect is selective for the tumour bed by virtue of i t s interaction with a tumour-derived factor. The interaction of FAA with host factors may be important for optimizing i t s therapeutic efficacy for a particular tumour.