Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease.

Clinical data clearly indicate a correlation between tumor neovascularization, aggressiveness of tumor growth, and metastatic spread. One of the key factors capable of stimulating tumor angiogenesis is vascular endothelial growth factor (VEGF). Using an immunoassay for VEGF, we assessed the levels of soluble VEGF in the sera and effusions of patients with malignant and nonmalignant disease as well as in the sera of healthy controls. Using a sandwich enzyme-linked immunoadsorbent assay, the concentration of VEGF was measured in serum specimens (n=445) and effusions (n=56) collected from a total of 212 patients with various types of cancer, 88 patients with nonmalignant disease, and 145 healthy individuals. Low and rather stable levels of VEGF were detected in the serum of healthy individuals (median, 294 pg/mL; range, 30-1752 pg/mL; 95th percentile, 883 pg/mL). Compared with healthy individuals, serum levels in patients with acute infections were elevated (P=0.03), whereas patients with chronic cirrhosis had lower serum VEGF levels. Among patients with various types of neoplasia, VEGF serum levels in patients with ovarian or gastrointestinal carcinoma were significantly higher than in healthy individuals. Moreover, VEGF concentrations in sera from patients with metastatic disease were higher than in sera from patients with localized tumors. Maximum serum concentrations of VEGF (median, 1022 pg/mL; range, 349-7821 pg/mL) were found in patients with metastatic ovarian carcinoma. Median VEGF levels (and ranges) in malignant effusions were up to 10-fold higher than in matched serum samples: 5528 pg/mL (468-49269 pg/mL) in ovarian carcinoma, 885 pg/mL (77-14,337 pg/mL) in breast carcinoma, and 813 pg/mL (372-18,331 pg/mL) in gastrointestinal carcinoma. In contrast, ascitic fluid from patients with cirrhosis contained only 303 pg/mL (median, range 116-676 pg/mL) of VEGF, corresponding to the low serum levels in this patient group. Depending on the tumor type, elevated levels of VEGF are detectable in the serum of only 0-20% of patients with localized cancer but in 11-65% of patients with metastatic cancer. Of cytology-proven malignant ascites or peritoneal exudates from various malignancies, 46-96% show VEGF levels above the upper limit (95th percentile, 676 pg/mL) of nonmalignant ascites. Maximum VEGF concentrations in malignant effusions indicate abundant local release of VEGF within the pleural or peritoneal cavity. These results suggest that VEGF might play an important role in tumor progression and the formation of malignant effusions. Further studies are warranted to determine the clinical value of soluble VEGF as a tumor marker, a prognostic factor, and a surrogate indicator of tumor angiogenesis.