Dual antivascular function of human fibulin‐3 variant, a potential new drug discovery strategy for glioblastoma
Autor: | Jun‐ran Luo, Jing Wang, Grace J. Gibson, Kody N. Le, Jesica R. Winokan, Yi-Hong Zhou, Zi‐wen Cen, Eric R. Siegel, Kambiz Afrasiabi, Zhongping Chen, Hai-Ping Cai, Asia E. McSwain, Yanyan Li, Furong Chen, Youxin Zhou, Mark E. Linskey, Chao Ke |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
CD31 Cancer Research Angiogenesis Nude Gene Expression Mice 0302 clinical medicine Drug Discovery Epidermal growth factor receptor Inbred BALB C vasculogenic mimicry Extracellular Matrix Proteins Mice Inbred BALB C Tumor Neovascularization Pathologic biology Brain Neoplasms extracellular compartment Chemistry Pharmacology and Pharmaceutical Sciences General Medicine ErbB Receptors Endothelial stem cell Oncology 030220 oncology & carcinogenesis Female Original Article Signal Transduction Oncology and Carcinogenesis Down-Regulation Mice Nude Cell Line 03 medical and health sciences Cell Line Tumor Animals Humans Vasculogenic mimicry Oncology & Carcinogenesis Protein kinase B Neovascularization Cell Proliferation Pathologic novel cancer therapeutic Matrigel Endothelial Cells Original Articles malignant glioma Xenograft Model Antitumor Assays Fibulin Drug Discovery and Delivery 030104 developmental biology Cancer research biology.protein Glioblastoma syngeneic primary culture |
Zdroj: | Cancer Science Cancer science, vol 111, iss 3 |
ISSN: | 1349-7006 1347-9032 |
DOI: | 10.1111/cas.14300 |
Popis: | 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. Vascularization in glioblastoma multiforme intracranial xenograft was reduced by intratumoral injection of ZR30, an in vitro synthesized 39‐kDa protein of human fibulin‐3 variant. |
Databáze: | OpenAIRE |
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