VASCULAR-PERMEABILITY FACTOR (VASCULAR ENDOTHELIAL GROWTH-FACTOR) IN GUINEA-PIG AND HUMAN TUMOR AND INFLAMMATORY EFFUSIONS

Vascular permeability factor (VPF), also known as vascular endothelial growth factor, is a dimeric M(r) 34,000-42,000 glycoprotein that poss esses potent vascular permeability-enhancing and endothelial cell-spec ific mitogenic activities. It is synthesized by many rodent and human tumor cells and also by some normal cells. Recently we developed a sen sitive and specific time-resolved immunofluorometric assay for quantif ying VPF in biological fluids. We here report findings with this assay in guinea pigs and patients with both malignant and nonmalignant effu sions. Line 1 and line 10 tumor cells were injected into the peritonea l cavities of syngeneic strain 2 guinea pigs, and ascitic fluid, plasm a. and urine were collected at various intervals. Within 2 to 4 days, we observed a time-dependent, parallel increase in VPF, ascitic fluid volume, and tumor cell numbers in animals bearing either tumor line; i n contrast, VPF was not detected in plasma or urine, even in animals w ith extensive tumor burdens. However, low levels of VPF were detected in the inflammatory ascites induced by i.p. oil injection. In human st udies, high levels of VPF (> 10 pM) were measured in 21 of 32 effusion s with cytology-documented malignant cells and in only seven of 35 eff usions without cytological evidence of malignancy. Thus, VPF levels in human effusions provided a diagnostic test for malignancy with a sens itivity of 66% and a specificity of 80% (perhaps as high as 97% in tha t six of the seven cytology-negative patients with VPF levels > 10 pM had cancer as determined by other criteria). As in the animal tumor mo dels, VPF was not detected in serum or urine obtained from patients wi th or without malignant ascites. Many nonmalignant effusions contained measurable VPF but, on average, in significantly smaller amounts than were found in malignant effusions. VPF levels in such fluids correlat ed strongly (rho = 0.59, P < 0.001) with monocyte and macrophage conte nt. Taken together, these data relate ascitic fluid accumulation to VP F concentration in a well-defined animal tumor system and demonstrate, for the first time, the presence of VPF in human malignant effusions. It is likely that VPF expression by tumor and mononuclear cells contr ibutes to the plasma exudation and fluid accumulation associated with malignant and certain inflammatory effusions. The VPF assay may prove useful for cancer diagnosis as a supplement to cytology, especially in tumors that grow in the pleural lining but not as a suspension in the effusions that they induce.