Grant Derrick S, Yenisey Cigdem, Rose R Wesley, Tootell Mason, Santra Manoranjan, Iozzo Renato V
Cardeza Foundation for Hematologic Research, Department of Medicine, Thomas Jefferson University, Room 812 Curtis Building, 1015 Walnut Street, Philadelphia, Pennsylvania, PA 19107, USA.
Oncogene. 2002 Jul 18;21(31):4765-77. doi: 10.1038/sj.onc.1205595.
The progressive growth of most neoplasms is dependent upon the establishment of new blood vessels, a process regulated by tumor-secreted factors and matrix proteins. We examined the in vitro and in vivo angiogenic ability of conditioned media obtained from fibrosarcoma, carcinoma, and osteosarcoma cells and their decorin-transfected counterparts. Human endothelial cells were investigated in vitro by evaluating three essential steps of angiogenesis: migration, attachment, and differentiation. On the whole, wild-type tumor cell-secretions enhanced endothelial cell attachment, migration, and differentiation, whereas their decorin-expressing forms inhibited these processes. Similarly, decorin-containing media suppressed endothelial cell sprouting in an ex vivo aortic ring assay. Since angiogenesis is an important component of tumor expansion, the growth rate of these cells as tumor xenografts was examined by implantation in nude mice. In vivo, the decorin-expressing tumor xenografts grew at markedly lower rates and showed a significant suppression of neovascularization. Immunohistochemical, Northern and Western blot analyses indicated that the decorin-expressing cells produced vascular endothelial growth factor (VEGF) at markedly reduced rates vis-á-vis their wild-type counterparts. Specificity of this process was confirmed by experiments where addition of recombinant decorin to the wild-type tumor cells caused 80-95% suppression of VEGF mRNA and protein. These results provide a novel mechanism of action for decorin, and indicate that decorin could adversely affect in vivo tumor growth by suppressing the endogenous tumor cell production of a powerful angiogenic stimulus.
大多数肿瘤的渐进性生长依赖于新血管的形成，这一过程受肿瘤分泌因子和基质蛋白调控。我们检测了从纤维肉瘤、癌和骨肉瘤细胞及其转染了核心蛋白聚糖的对应细胞获得的条件培养基的体外和体内血管生成能力。通过评估血管生成的三个关键步骤：迁移、黏附和分化，对人内皮细胞进行了体外研究。总体而言，野生型肿瘤细胞分泌物增强了内皮细胞的黏附、迁移和分化，而其表达核心蛋白聚糖的形式则抑制了这些过程。同样，含有核心蛋白聚糖的培养基在体外主动脉环试验中抑制了内皮细胞的芽生。由于血管生成是肿瘤扩展的重要组成部分，通过将这些细胞植入裸鼠体内，检测了它们作为肿瘤异种移植物的生长速率。在体内，表达核心蛋白聚糖的肿瘤异种移植物生长速率明显较低，并且显示出新生血管形成受到显著抑制。免疫组织化学、Northern印迹和Western印迹分析表明，与野生型对应细胞相比，表达核心蛋白聚糖的细胞产生血管内皮生长因子（VEGF）的速率明显降低。向野生型肿瘤细胞中添加重组核心蛋白聚糖导致VEGF mRNA和蛋白抑制80 - 95%的实验证实了这一过程的特异性。这些结果为核心蛋白聚糖提供了一种新的作用机制，并表明核心蛋白聚糖可能通过抑制内源性肿瘤细胞产生强大的血管生成刺激而对体内肿瘤生长产生不利影响。
