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.
Flavone acetic acid (FAA) is a potentially useful anti-tumour 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 blockade 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 (half-maximal at 0.6-0.7 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 its interaction with tumour-derived factors. Starting with serum-free FO-I-melanoma 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 endothelial-cell-tissue factor. This activity is not found in supernatants from non-neoplastically transformed cell lines. These data lead us to hypothesize that FAA exerts its 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 its interaction with a tumour-derived factor. The interaction of FAA with host factors may be important for optimizing its therapeutic efficacy for a particular tumour.
Murray
J C
JC
Cancer Research Campaign, Gray Laboratory, Mount Vernon Hospital, Northwood, Middlesex, UK.
Clauss
M
M
Denekamp
J
J
Stern
D
D
D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D003470:Culture Media / Q000737:chemistry; D004730:Endothelium, Vascular / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000098:blood supply / Q000378:metabolism*; D008970:Molecular Weight; D013925:Thromboplastin / Q000096:biosynthesis* / Q000302:isolation & purification; D014407:Tumor Cells, Cultured / Q000378:metabolism
D001779:Blood Coagulation Factors; D003470:Culture Media; D005419:Flavonoids; C053675:endothelial cell procoagulant activity; C049328:flavone acetic acid; D013925:Thromboplastin