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Departments of Pathology [K-T. Y., H. H. W., J. A. N., T. M. S., Y. Z., E. M. M., D. R. S., H. F. D., T-K. Y.], Beth Israel Hospital and Harvard Medical School, Boston, Massachusetts 02215, and Cancer and Infectious Disease Research [S. R. L., A. J. H.], The Upjohn Company, Kalamazoo, Michigan 49001
Vascular permeability factor (VPF), also known as vascular endothelial growth factor, is a dimeric Mr 34,000–42,000 glycoprotein that possesses potent vascular permeability-enhancing and endothelial cell-specific mitogenic activities. It is synthesized by many rodent and human tumor cells and also by some normal cells. Recently we developed a sensitive and specific time-resolved immunofluorometric assay for quantifying VPF in biological fluids. We here report findings with this assay in guinea pigs and patients with both malignant and nonmalignant effusions. Line 1 and line 10 tumor cells were injected into the peritoneal cavities of syngeneic strain 2 guinea pigs, and ascitic fluid, plasma, 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; in contrast, VPF was not detected in plasma or urine, even in animals with extensive tumor burdens. However, low levels of VPF were detected in the inflammatory ascites induced by i.p. oil injection. In human studies, high levels of VPF (> 10 pM) were measured in 21 of 32 effusions with cytology-documented malignant cells and in only seven of 35 effusions without cytological evidence of malignancy. Thus, VPF levels in human effusions provided a diagnostic test for malignancy with a sensitivity of 66% and a specificity of 80% (perhaps as high as 97% in that six of the seven cytology-negative patients with VPF levels > 10 pM had cancer as determined by other criteria). As in the animal tumor models, VPF was not detected in serum or urine obtained from patients with 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 correlated strongly (
= 0.59, P < 0.001) with monocyte and macrophage content. Taken together, these data relate ascitic fluid accumulation to VPF 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 contributes to the plasma exudation and fluid accmumulation 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.
1 This work was supported by USPHS NIH Grants CA-50453 and CA-58845 (to H. F. D.) and CA-43967 (to D. R. S.) from the National Cancer Institute; by the BIH Pathology Foundation, Inc.; and under terms of a contract from the National Foundation for Cancer Research.
2 To whom requests for reprints should be addressed, at Department of Pathology, Beth Israel Hospital, 330 Brookline Ave., Boston, MA 02215.
3 Present address: Department of Pathology, S.U.N.Y. at Stony Brook, Stony Brook, NY 11794.
Received 1/25/93. Accepted 4/ 8/93.
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