Weber Michael H, Lee Joanne, Orr F William
Department of Pathology, University of Manitoba, Winnipeg, Manitoba R3E 0W3, Canada.
Int J Oncol. 2002 Feb;20(2):299-303.
Bone metastases are generally associated with bone destruction which occurs in response to factors secreted by metastatic cells. Some of these factors secreted by the metastatic cells activate osteoclats while others are proteases that degrade bone collagen. To determine if Neovastat (AE-941), a naturally occurring multi-functional inhibitor of angiogenesis, is able to regulate properties that are thought to have relevance to their propensity to form bone metastases in vivo, we used the human breast cancer MDA-MB-231 cell line which can metastasize to bone. We showed that Neovastat prevented the degradation of osteoid-like radiolabeled extracellular matrices which was induced by incubation of human SaOS-2 osteoblast-like cells with MDA-MB-231 cells. Moreover, Neovastat was demonstrated to inhibit the gelatinolytic activity of matrix metalloproteinase (MMP)-9 expressed by MDA-MB-231 cells. The potential of Neovastat to retard the spread, growth, and osteolysis of MDA-MB-231 cells was then estimated in vivo. Histomorphometric analysis of the vertebral bodies indicated that MDA-MB-231 cells inoculated in nude mice (intracardiac) successfully generate osteolytic metastases with an 83% reduction of the volume of medullary bone (p< or =0.01). However, when tumor-bearing animals were treated orally with Neovastat, there was only a 19% decrease in medullary bone thus indicating that Neovastat can prevent bone metastasis in this model. Consistent with histological results, radiographic analysis indicated that Neovastat decreased the number of osteolytic lesions by 33% (p< or =0.3). Moreover, a decrease in the tumor volume in bone was observed in Neovastat-treated animals. These results indicate that Neovastat may be useful in preventing bone metastasis in cancer patients.
骨转移通常与骨破坏相关，骨破坏是由转移细胞分泌的因子所引发的。转移细胞分泌的部分因子会激活破骨细胞，而其他一些则是降解骨胶原蛋白的蛋白酶。为确定天然存在的多功能血管生成抑制剂Neovastat（AE - 941）是否能够调节那些被认为与其在体内形成骨转移倾向相关的特性，我们使用了可转移至骨的人乳腺癌MDA - MB - 231细胞系。我们发现，Neovastat可防止类骨质放射性标记细胞外基质的降解，这种降解是由人SaOS - 2成骨样细胞与MDA - MB - 231细胞共培养所诱导的。此外，Neovastat还被证明可抑制MDA - MB - 231细胞表达的基质金属蛋白酶（MMP）- 9的明胶酶活性。随后在体内评估了Neovastat延缓MDA - MB - 231细胞扩散、生长及骨溶解的潜力。椎体的组织形态计量学分析表明，接种于裸鼠（心内注射）的MDA - MB - 231细胞成功形成了溶骨性转移灶，骨髓骨体积减少了83%（p≤0.01）。然而，当给荷瘤动物口服Neovastat时，骨髓骨仅减少了19%，这表明Neovastat在此模型中可预防骨转移。与组织学结果一致，影像学分析表明Neovastat使溶骨性病变数量减少了33%（p≤0.3）。此外，在接受Neovastat治疗的动物中还观察到骨内肿瘤体积减小。这些结果表明，Neovastat可能对预防癌症患者的骨转移有用。
