Dual antivascular function of human fibulin‐3 variant, a potential new drug discovery strategy for glioblastoma

Abstract

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.

<p>Advances and Prospects of Vasculogenic Mimicry in Glioma: A Potential New Therapeutic Target?</p>

“…An increasing number of studies have shown that GSCs play a vital role in the development of VM in glioma. 41 However, Ke et al 42 found that non-stem-like cells of glioma were more prone to gain VM-related gene expression and phenotype than were stem-like cells of the same origin.…”

EFEMP1 binds to STEAP1 to promote osteosarcoma proliferation and invasion via the Wnt/β-catenin and TGF-β/Smad2/3 signal pathways

“…EFEMP1 is secreted by glioma cells to promote angiogenesis, tumor invasion, and tumor cell survival. The development of blocking antibodies against EFEMP1 or truncation variants and other mutants by gene engineering may more be an effective therapeutic approach for malignant gliomas [25] , [26] . However, in breast cancer [27] and endometrial cancer [28] , [29] , EFEMP1 acts as a tumor suppressor gene, Low EFEMP1 levels predict adverse outcomes, and high EFEMP1 levels inhibit TGF-β-induced EMT, migration, and invasion.…”

Glioblastoma Vasculature: From its Critical Role in Tumor Survival to Relevant in Vitro Modelling

“…Matrigel has also shown utility in the study of GSC transdifferentiation into ECs. A tubular network assay with patient-derived GBM cells cultured on Matrigel was used to characterize GSCs and verify their vascular development ability (Ke et al, 2020). In this case, patient cells were able to transdifferentiate into ECs and further form tubular structures.…”

“…In this case, patient cells were able to transdifferentiate into ECs and further form tubular structures. Using the same model, researchers also tested drugs capable of inhibiting this transdifferentiation process (Ke et al, 2020). Furthermore, patient-derived GBM cells cultured on Matrigel have also been used to study GBM recurrence and resistance mechanisms after radiotherapy.…”