Dual antivascular function of human fibulin-3 variant, a potential new drug discovery strategy for glioblastoma
Dual antivascular function of human fibulin-3 variant, a potential new drug discovery strategy for glioblastoma
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人fibulin-3变体的双重抗血管功能，胶质母细胞瘤的潜在新药发现策略
DOI：
10.1111/cas.14300
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发表时间：
2020-03-01
期刊：
影响因子：
5.7
通讯作者：
Zhou, Yi-Hong
中科院分区：
文献类型：
--
作者：
Ke, Chao;Luo, Jun-ran;Zhou, Yi-Hong
ECM蛋白EFEMP1（纤维蛋白-3）通过其细胞环境依赖的双重功能与所有类型的实体瘤相关。通过截断和突变，设计了一种纤维蛋白-3的变体，以减轻其致癌功能，特别是在干细胞样状态的多形性胶质母细胞瘤（GBM）细胞中的促侵袭作用。ZR30是一种体外合成的39 kda的人纤维蛋白-3变异蛋白。它通过抑制GBM细胞中表皮生长因子受体/AKT和NOTCH1/AKT信号通路以及细胞外MMP2激活，对人GBM颅内异种移植模型有治疗作用。多形性胶质母细胞瘤是高度血管化的，由表达内皮细胞标志物（包括CD31）的肿瘤细胞形成渗漏的血管。在这里，我们通过CD31免疫组织化学研究了肿瘤内注射ZR30或PBS 2周后GBM颅内异种移植物。我们发现，与pbs处理的异种移植物相比，zr30处理的血管密度降低了70%。基质塞实验显示ZR30具有抑制血管生成的作用。我们进一步研究了ZR30在不同培养条件下对3种GBMs的7个原代培养中内皮转分化（ETD）相关基因的影响。两种GBM培养物在Matrigel基质中培养后不久形成网状结构，ETD基因表达上调，ZR30抑制了这两种结构。ZR30在两个高表达的GBM培养物中也下调了ETD基因。综上所述，人纤维蛋白3变异体在GBM中具有多方面的肿瘤抑制作用，包括抑制血管生成和血管生成模拟。
The ECM protein EFEMP1 (fibulin-3) is associated with all types of solid tumor through its cell context-dependent dual function. A variant of fibulin-3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem-like state. ZR30 is an in vitro synthesized 39-kDa protein of human fibulin-3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30-treated xenografts compared with that of PBS-treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin-3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.