A polypeptide factor produced by fibrosarcoma cells that induces endothelial tissue factor and enhances the procoagulant response to tumor necrosis factor/cachectin.
Intravascular clot formation, localized to the neoplasm, is an early component of the vascular response to tumor necrosis factor (TNF)/cachectin. Fibrin is closely associated with the endothelial cell surface, and multiple microthromboses lead to reduced blood flow in the tumor. We have identified a tumor-derived mediator which enhances endothelial procoagulant activity and the cellular response to TNF using cultured cells derived from a murine methylcholanthrene A (meth A)-induced fibrosarcoma as a model system. A heat-stable protease K-sensitive polypeptide, Mr approximately 44,000 on nonreduced sodium dodecyl sulfate-polyacrylamide gel electrophoresis (Mr approximately 56,000 reduced), was purified approximately 500,000-fold from serum-free culture supernatants of meth A cells by sequential Q-Sepharose, Mono S, reversed phase, and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Based on immunologic criteria, biologic activity, and other molecular properties, meth A factor appears to be distinct from other cytokines and growth factors. Purified meth A factor induced transcription of the tissue factor gene and expression of procoagulant activity by cultured human endothelium (half-maximal effect for the latter at approximately 6-8 pM). Furthermore, co-incubation of endothelium with meth A factor together with TNF enhanced induction of tissue factor in a more than additive manner. These data indicate that certain tumors elaborate an apparently unique molecule which can alter hemostatic properties of the vessel wall, potentially modulating reactivity of the tumor vasculature to host response mediators.
Clauss
M
M
Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032.
Murray
J C
JC
Vianna
M
M
de Waal
R
R
Thurston
G
G
Nawroth
P
P
Gerlach
H
H
Bach
R
R
Familletti
P C
PC
Stern
D
D
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005354:Fibrosarcoma / Q000503:physiopathology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008748:Methylcholanthrene; D051379:Mice; D008970:Molecular Weight; D009363:Neoplasm Proteins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D008748:Methylcholanthrene; D013925:Thromboplastin