Neill Thomas, Schaefer Liliana, Iozzo Renato V
Department of Pathology, Anatomy and Cell Biology, Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Pharmacology, Goethe University, 60590 Frankfurt, Germany.
Adv Drug Deliv Rev. 2016 Feb 1;97:174-85. doi: 10.1016/j.addr.2015.10.016. Epub 2015 Oct 30.
Decorin is a prototypical small leucine-rich proteoglycan that epitomizes the multifunctional nature of this critical gene family. Soluble decorin engages multiple receptor tyrosine kinases within the target-rich environment of the tumor stroma and tumor parenchyma. Upon receptor binding, decorin initiates signaling pathways within endothelial cells downstream of VEGFR2 that ultimately culminate in a Peg3/Beclin 1/LC3-dependent autophagic program. Concomitant with autophagic induction, decorin blunts capillary morphogenesis and endothelial cell migration, thereby significantly compromising tumor angiogenesis. In parallel within the tumor proper, decorin binds multiple RTKs with high affinity, including Met, for a multitude of oncosuppressive functions including growth inhibition, tumor cell mitophagy, and angiostasis. Decorin is also pro-inflammatory by modulating macrophage function and cytokine secretion. Decorin suppresses tumorigenic growth, angiogenesis, and prevents metastatic lesions in a variety of in vitro and in vivo tumor models. Therefore, decorin would be an ideal therapeutic candidate for combating solid malignancies.
核心蛋白聚糖是富含亮氨酸的蛋白聚糖家族中的典型小分子，它体现了这个关键基因家族的多功能特性。可溶性核心蛋白聚糖在肿瘤基质和肿瘤实质富含靶点的环境中与多种受体酪氨酸激酶相互作用。与受体结合后，核心蛋白聚糖在血管内皮生长因子受体2（VEGFR2）下游的内皮细胞内启动信号通路，最终导致依赖Peg3/Beclin 1/LC3的自噬程序。伴随自噬诱导，核心蛋白聚糖抑制毛细血管形态发生和内皮细胞迁移，从而显著损害肿瘤血管生成。在肿瘤内部，核心蛋白聚糖还以高亲和力结合多种受体酪氨酸激酶，包括Met，发挥多种肿瘤抑制功能，如生长抑制、肿瘤细胞线粒体自噬和血管生成抑制。核心蛋白聚糖还通过调节巨噬细胞功能和细胞因子分泌而具有促炎作用。在多种体外和体内肿瘤模型中，核心蛋白聚糖可抑制肿瘤生长、血管生成并预防转移灶形成。因此，核心蛋白聚糖将是对抗实体恶性肿瘤的理想治疗候选药物。
