Warren R S, Yuan H, Matli M R, Gillett N A, Ferrara N
Department of Surgery, University of California School of Medicine, San Francisco 94143, USA.
J Clin Invest. 1995 Apr;95(4):1789-97. doi: 10.1172/JCI117857.
To investigate the relationship between angiogenesis and hepatic tumorigenesis, we examined the expression of vascular endothelial growth factor (VEGF) in 8 human colon carcinoma cell lines and in 30 human colorectal cancer liver metastases. Abundant message for VEGF was found in all tumors, localized to the malignant cells within each neoplasm. Two receptors for VEGF, KDR and flt1, were also demonstrated in most of the tumors examined. KDR and flt1 mRNA were limited to tumor endothelial cells and were more strongly expressed in the hepatic metastases than in the sinusoidal endothelium of the surrounding liver parenchyma. VEGF monoclonal antibody administration in tumor-bearing athymic mice led to a dose- and time-dependent inhibition of growth of subcutaneous xenografts and to a marked reduction in the number and size of experimental liver metastases. In hepatic metastases of VEGF antibody-treated mice, neither blood vessels nor expression of the mouse KDR homologue flk-1 could be demonstrated. These data indicate that VEGF is a commonly expressed angiogenic factor in human colorectal cancer metastases, that VEGF receptors are up-regulated as a concomitant of hepatic tumorigenesis, and that modulation of VEGF gene expression or activity may represent a potentially effective antineoplastic therapy in colorectal cancer.
为了研究血管生成与肝肿瘤发生之间的关系，我们检测了8种人结肠癌细胞系和30例人结直肠癌肝转移灶中血管内皮生长因子（VEGF）的表达。在所有肿瘤中均发现了丰富的VEGF信息，其定位于每个肿瘤内的恶性细胞。在所检测的大多数肿瘤中也证实了VEGF的两种受体KDR和flt1。KDR和flt1 mRNA仅限于肿瘤内皮细胞，并且在肝转移灶中的表达比周围肝实质的窦状内皮细胞更强。给荷瘤无胸腺小鼠注射VEGF单克隆抗体导致皮下异种移植物生长受到剂量和时间依赖性抑制，并使实验性肝转移灶的数量和大小显著减少。在VEGF抗体处理小鼠的肝转移灶中，既未发现血管，也未检测到小鼠KDR同源物flk-1的表达。这些数据表明，VEGF是人类结直肠癌转移中普遍表达的血管生成因子，VEGF受体随着肝肿瘤发生而被上调，并且调节VEGF基因表达或活性可能代表结直肠癌一种潜在有效的抗肿瘤治疗方法。
