Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration.

TLDR

Systemic infusion of low concentrations of tumor necrosis factor/cachectin (TNF) into mice bearing TNF‑sensitive tumors activates coagulation, induces fibrin formation, and causes occlusive thrombosis exclusively within the tumor vascular bed. The study aims to identify mechanisms underlying the localization of this tumor‑associated vascular procoagulant response. The authors purified a tumor‑derived polypeptide from murine methylcholanthrene A‑induced fibrosarcoma supernatants, which induces endothelial tissue factor synthesis at ~300 pM and synergistically augments TNF‑induced procoagulant activity. The purified polypeptide, identified as the murine homologue of vascular permeability factor (VPF), induces endothelial tissue factor synthesis, activates monocytes to express tissue factor, promotes monocyte chemotaxis across collagen and endothelial layers, and thereby modulates endothelial and monocyte coagulant activity and facilitates monocyte migration into the tumor bed, illustrating how tumor‑derived mediators can alter vessel wall properties.

Abstract

Systemic infusion of low concentrations of tumor necrosis factor/cachectin (TNF) into mice that bear TNF-sensitive tumors leads to activation of coagulation, fibrin formation, and occlusive thrombosis exclusively within the tumor vascular bed. To identify mechanisms underlying the localization of this vascular procoagulant response, a tumor-derived polypeptide has been purified to homogeneity from supernatants of murine methylcholanthrene A-induced fibrosarcomas that induces endothelial tissue factor synthesis and expression (half-maximal response at approximately 300 pM), and augments the procoagulant response to TNF in a synergistic fashion. This tumor-derived polypeptide was identified as the murine homologue of vascular permeability factor (VPF) based on similar mobility on SDS-PAGE, an homologous NH2-terminal amino acid sequence, and recognition by a monospecific antibody to guinea pig VPF. In addition, VPF was shown to induce monocyte activation, as evidenced by expression of tissue factor. Finally, VPF was shown to induce monocyte chemotaxis across collagen membranes and endothelial cell monolayers. Taken together, these results indicate that VPF can modulate the coagulant properties of endothelium and monocytes, and can promote monocyte migration into the tumor bed. This suggests one mechanism through which tumor-derived mediators can alter properties of the vessel wall.