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
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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