Wickström Sara A, Alitalo Kari, Keski-Oja Jorma
Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum Helsinki and Helsinki University Hospital, FIN-00014 Helsinki, Finland.
Adv Cancer Res. 2005;94:197-229. doi: 10.1016/S0065-230X(05)94005-0.
The growth and survival of a malignant tumor are dependent on the formation and maintenance of its own microvasculature, a process termed angiogenesis. Inhibition of this phenomenon is an emerging strategy in cancer therapy. The extracellular matrix surrounding the vascular endothelial cells contains cryptic protein domains, which are exposed by changes in the proteolytic homeostasis of the tumor microenvironment. These fragments transmit local signals, which regulate vascular endothelial cell proliferation and migration. Endostatin, the proteolytic fragment of collagen type XVIII, is a potent inhibitor of tumor angiogenesis in various mouse models and is currently in clinical trials for therapeutic use in human cancer. Multiple cell surface receptors have been described for endostatin, but the signals transmitted by these receptors resulting in the inhibition of angiogenesis have so far been poorly characterized. Studies on the effects of endostatin on cultured endothelial cells suggest that the antimigratory and antiproliferative properties of this molecule are the major mechanisms underlying its antiangiogenic potential. These effects may be a consequence of endostatin modulation of endothelial cell-matrix interactions and pericellular proteolysis.
恶性肿瘤的生长与存活依赖于其自身微血管系统的形成与维持，这一过程称为血管生成。抑制这一现象是癌症治疗中一种新兴的策略。血管内皮细胞周围的细胞外基质含有隐蔽的蛋白质结构域，这些结构域会因肿瘤微环境中蛋白水解稳态的变化而暴露。这些片段传递局部信号，调节血管内皮细胞的增殖和迁移。内皮抑素是 XVIII 型胶原蛋白的蛋白水解片段，在多种小鼠模型中是一种有效的肿瘤血管生成抑制剂，目前正处于用于人类癌症治疗的临床试验阶段。已描述了内皮抑素的多种细胞表面受体，但迄今为止，这些受体所传递的导致血管生成抑制的信号仍未得到充分表征。对内皮抑素对培养的内皮细胞作用的研究表明，该分子的抗迁移和抗增殖特性是其抗血管生成潜力的主要机制。这些作用可能是内皮抑素调节内皮细胞与基质相互作用及细胞周围蛋白水解的结果。
