Association of serum endoglin with metastasis in patients with colorectal, breast, and other solid tumors, and suppressive effect of chemotherapy on the serum endoglin

Abstract

In this report, we present data indicating that the increased serum endoglin (EDG; CD105) quantitated by a double-antibody sandwich assay is associated with metastasis in patients with solid tumors including colorectal and breast carcinomas. In addition, we show that chemotherapy exerts a suppressive effect on the serum EDG. EDG is a proliferation-associated cell membrane antigen of human vascular endothelial cells. Furthermore, EDG is essential for angiogenesis. We generated two anti-EDG monoclonal antibodies (mAbs), termed SN6a and SN6h, defining different epitopes of EDG and developed a double-antibody sandwich assay to quantitate serum EDG in patients with solid tumors. SN6h possesses an exceedingly high antigen-binding avidity (K, 1.38 x 10(11) liters/mol), whereas SN6a possesses an ordinary avidity for a mAb directed to a cell surface antigen (K, 2.85 x 10(8) liters/mol). We measured serum samples from 101 patients with solid tumors (34 colorectal cancers, 16 breast cancers, and 51 other cancers), 8 patients with benign diseases, and 31 healthy volunteers. The serum level of EDG was significantly elevated in the patients with metastatic cancers. The mean serum EDG in the 42 metastasis-negative patients was 34.0 +/- 26.8 ng/ml (median value, 27.9 ng/ml), whereas the value in the 59 metastasis-positive patients was 63.8 +/- 72.5 ng/ml (median value, 37.2 ng/ml). The difference in EDG levels between the two groups was statistically significant (P = 0.012). Of the colorectal cancer patients, the difference in EDG levels between the 19 metastasis-negative patients and the 15 metastasis-positive patients was statistically significant (P = 0.02). In addition, the difference between the normal control (n = 31) and the 15 metastasis-positive colorectal cancer patients was statistically significant (P = 0.04). Of the breast cancer patients, the difference in EDG levels between the 11 metastasis-positive patients and the normal control was statistically significant (P < 0.005). In additional studies, we found that chemotherapy suppressed serum EDG levels in cancer patients. Of the 54 metastasis-positive patients with solid tumors, the mean serum EDG in the 32 chemotherapy-receiving [chemotherapy(+)] patients was 44.7 +/- 41.9 ng/ml (median value, 36.1 ng/ml), whereas the value in the 22 chemotherapy(-) patients was 102.4 +/- 99.5 ng/ml (median value, 64.8 ng/ml). The difference in serum EDG between the two groups is statistically significant (P < 0.005). In the majority of metastasis-positive patients who were not receiving chemotherapy, serum EDG was elevated. The results suggest that serum EDG may be a useful marker for monitoring early signs of metastasis and cancer relapse in a long-term follow-up of solid tumor patients.