INTRAVENOUS SOMATIC GENE-TRANSFER WITH ANTISENSE TISSUE FACTOR RESTORES BLOOD-FLOW BY REDUCING TUMOR NECROSIS FACTOR-INDUCED TISSUE FACTOR EXPRESSION AND FIBRIN DEPOSITION IN MOUSE METH-A SARCOMAS

Fibrin is deposited on the endothelial cell surface in the vasculature of murine methylcholanthrene A-induced sarcomas after injection of tu mor necrosis factor (TNF). Capillary endothelial cells of the tumor va scular bed become positive for tissue factor after TNF injection, base d on immunocytochemistry and in situ hybridization. Intravascular dot formation was not dependent on tissue factor derived from tumor cells, since in vessels of tumors not expressing tissue factor, TNF also ind uced fibrin/fibrinogen deposition. However, the time course of fibrin/ fibrinogen deposition after TNF differed in tumors expressing no, litt le, or greater amounts of tissue factor. Fibrin/fibrinogen deposition was more rapid in tumors in which the neoplastic cells expressed tissu e factor than in tumors not expressing tissue factor. In the tumors no t expressing tissue factor, activation of coagulation was dependent on TNF-induced synthesis of tissue factor by host cells, i.e., endotheli um or monocytes/macrophages. Intravenous somatic gene transfer with ti ssue factor cDNA in the antisense orientation (but not sense or vector alone) reduced intravascular fibrin/fibrinogen deposition and restore d blood flow to the tumor, showing that de novo tissue factor expressi on is central in TNF-induced activation of the coagulation mechanism.