Bone Morphogenetic Protein 4 Targeting Glioma Stem-Like Cells for Malignant Glioma Treatment: Latest Advances and Implications for Clinical Application

Abstract

Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicates its potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, with an emphasis on pediatric malignant gliomas. We also summarize BMP4 delivery strategies, highlighting biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.

A Novel Role of BIRC3 in Stemness Reprogramming of Glioblastoma

“…BMP4 is strongly associated with GBM stem cell differentiation [ 29 , 30 , 31 ], and has been reported as a potential anti-GBM target [ 32 ]. Since BIRC3 expression is associated with GBM cell self-renewal and stemness maintenance, we wanted to determine if there was any correlation between BIRC3 expression and BMP4 signaling activation.…”

Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years

“…BMPs suppress the tumorigenic function of human glioma-initiating cells by inducing cell differentiation, cell cycle arrest, and apoptosis (see below). Accordingly, several reports have shown that BMP-4 is expressed in low-grade gliomas, and that it serves as a favorable prognostic marker in gliomas ( Bao et al, 2013 ; Nayak et al, 2020 ). BMP-4 is overexpressed in gliomas harboring IDH1 mutations, which are a hallmark of better prognosis ( Zhou et al, 2020 ).…”

Overexpression of Cystine/Glutamate Antiporter xCT Correlates with Nutrient Flexibility and ZEB1 Expression in Highly Clonogenic Glioblastoma Stem-like Cells (GSCs)

“…Bone morphogenic protein 4 (BMP4) has previously been shown to effectively reduce the GSC pool in GBM [ 30 ]. As a proof of principle, we treated highly clonogenic JHH520 and 407 cells with 50 ng/mL BMP4 for 48 h and observed significantly increased expression of the differentiation marker glial fibrillary acidic protein ( GFAP ) and reduced expression of two stemness markers ( CD133 and SOX2 ).…”