Takahashi N, Kawanishi-Tabata R, Haba A, Tabata M, Haruta Y, Tsai H, Seon B K
Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Clin Cancer Res. 2001 Mar;7(3):524-32.
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.
在本报告中，我们展示的数据表明，通过双抗体夹心测定法定量的血清内皮糖蛋白（EDG；CD105）升高与包括结直肠癌和乳腺癌在内的实体瘤患者的转移相关。此外，我们表明化疗对血清EDG有抑制作用。EDG是人类血管内皮细胞的一种与增殖相关的细胞膜抗原。此外，EDG对血管生成至关重要。我们制备了两种抗EDG单克隆抗体（mAb），分别称为SN6a和SN6h，它们定义了EDG的不同表位，并开发了一种双抗体夹心测定法来定量实体瘤患者的血清EDG。SN6h具有极高的抗原结合亲和力（K，1.38×10¹¹升/摩尔），而SN6a对于针对细胞表面抗原的单克隆抗体具有普通亲和力（K，2.85×10⁸升/摩尔）。我们检测了101例实体瘤患者（34例结直肠癌、16例乳腺癌和51例其他癌症）、8例良性疾病患者和31名健康志愿者的血清样本。转移性癌症患者的血清EDG水平显著升高。42例无转移患者的血清EDG平均水平为34.0±26.8 ng/ml（中位数为27.9 ng/ml），而59例有转移患者的值为63.8±72.5 ng/ml（中位数为37.2 ng/ml）。两组之间EDG水平的差异具有统计学意义（P = 0.012）。在结直肠癌患者中，19例无转移患者和15例有转移患者之间的EDG水平差异具有统计学意义（P = 0.02）。此外，正常对照组（n = 31）与15例有转移的结直肠癌患者之间的差异具有统计学意义（P = 0.04）。在乳腺癌患者中，11例有转移患者与正常对照组之间的EDG水平差异具有统计学意义（P < 0.005）。在进一步的研究中，我们发现化疗可抑制癌症患者的血清EDG水平。在54例有转移的实体瘤患者中，32例接受化疗[化疗（+）]患者的血清EDG平均水平为44.7±41.9 ng/ml（中位数为36.1 ng/ml），而22例未接受化疗[化疗（-）]患者的值为102.4±99.5 ng/ml（中位数为64.8 ng/ml）。两组之间血清EDG的差异具有统计学意义（P < 0.005）。在大多数未接受化疗的有转移患者中，血清EDG升高。结果表明，血清EDG可能是实体瘤患者长期随访中监测转移和癌症复发早期迹象的有用标志物。
