Aoka Yoshikazu, Johnson Frances L, Penta Kalyani, Hirata Ki Ken-ichi, Hidai Chiaki, Schatzman Randall, Varner Judith A, Quertermous Thomas
Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk CVRC, 300 Pasteur Drive, Stanford, California 94305, USA.
Microvasc Res. 2002 Jul;64(1):148-61. doi: 10.1006/mvre.2002.2414.
Del1 is a unique alpha v beta 3 integrin ligand that is produced by endothelial cells, and thus provides an autocrine signaling pathway in this cell type. It is expressed transiently in the embryo and mediates cell attachment, migration, and activation of cytoplasmic signaling molecules in focal contacts. Del1 also activates angiogenesis in the chick chorioallantoic membrane assay. Reexpression of this embryonic signaling molecule has now been documented in naturally occurring human tumors, where it is expressed by both tumor cells and angiogenic endothelial cells, suggesting that Del1 is important in mediating angiogenesis under pathophysiological conditions in the adult. To investigate the role of Del1 in tumor growth and angiogenesis, human 143B osteosarcoma cells and murine Lewis lung carcinoma cells were engineered to express Del1 and compared to control transfectants for their ability to produce tumors in nude or syngeneic mice, respectively. Del1 expressing tumors showed a two- to fourfold increase in capillary density and an accelerated rate of growth. Expression of Del1 also correlated with a decrease in apoptosis in tumor cells in vivo. Taken together, these data suggest that Del1 acts as an angiogenic factor in the context of solid tumor formation and that this increase in vascularization accelerates tumor growth through decreased apoptosis.
Del1是一种由内皮细胞产生的独特的αvβ3整合素配体，因此在这种细胞类型中提供了一条自分泌信号通路。它在胚胎中短暂表达，并介导细胞附着、迁移以及粘着斑中细胞质信号分子的激活。Del1在鸡胚绒毛尿囊膜试验中也能激活血管生成。现已证明，这种胚胎信号分子在自然发生的人类肿瘤中重新表达，肿瘤细胞和血管生成内皮细胞均表达该分子，这表明Del1在介导成人病理生理条件下的血管生成中起重要作用。为了研究Del1在肿瘤生长和血管生成中的作用，对人143B骨肉瘤细胞和鼠Lewis肺癌细胞进行基因改造以表达Del1，并分别与对照转染细胞比较其在裸鼠或同基因小鼠中产生肿瘤的能力。表达Del1的肿瘤毛细血管密度增加了两到四倍，生长速度加快。Del1的表达还与体内肿瘤细胞凋亡的减少相关。综上所述，这些数据表明Del1在实体瘤形成过程中作为一种血管生成因子发挥作用，并且这种血管化增加通过减少凋亡加速肿瘤生长。
