Emx2as a novel tool to suppress glioblastoma

Abstract

Glioblastoma is a devastating CNS tumour for which no cure is presently available. We wondered if manipulation of Emx2, which normally antagonizes cortico-cerebral astrogenesis by inhibiting proliferation of astrocyte progenitors, may be employed to counteract it. We found that Emx2 overexpression induced the collapse of seven out of seven in vitro tested glioblastoma cell lines. Moreover, it suppressed four out of four of these lines in vivo. As proven by dedicated rescue assays, the antioncogenic activity of Emx2 originated from its impact on at least six metabolic nodes, which accounts for the robustness of its effect. Finally, in two out of two tested lines, the tumor culture collapse was also achieved when Emx2 was driven by a neural stem cell-specific promoter, likely active within tumor-initiating cells. All that points to Emx2 as a novel, promising tool for therapy of glioblastoma and prevention of its recurrencies.

Different Effects of Human Umbilical Cord Mesenchymal Stem Cells on Glioblastoma Stem Cells by Direct Cell Interaction or Via Released Soluble Factors

“…These results were confirmed by qRT-PCR, showing increased GFAP mRNA levels in differentiated cells from all the three GBMs as compared to the respective CSCs (Figure 2C ). All GBM CSC cultures used in this study have been evaluated in previous experiments for the ability to form tumors when orthotopically xenotransplanted in the brain of NOD/SCID mice, confirming the retaining of tumorigenic activity even after prolonged in vitro growth (Corsaro et al, 2016 ; Falcone et al, 2016 ).…”

The expression of EMX2 lead to cell cycle arrest in glioblastoma cell line

“…Indeed, EMX2 has a documented anti-proliferative effect in vitro and anti-tumorigenesis effect in vivo in some solid cancers [ 28 , 45 – 47 ]. In GB cell culture, Falcone et al reported that proliferation inhibition induced by EMX2 was associated with cell collapse and apoptosis activity within 7–8 days [ 31 ]. We did not observe enhanced cell death until 7 days of culture, and we observed no sign of apoptosis over 16 days of culture.…”

“…Furthermore, EMX2 expression has documented prognostic and/or predictive values for survival of malignant pleural mesothelioma [ 29 ] and lung adenocarcinoma [ 30 ]. Recently, Falcone et al reported that EMX2 overexpression suppresses GB growth both in vitro and in vivo, and induces apoptosis in GB cells [ 31 ].…”

Glioblastoma: new therapeutic strategies to address cellular and genomic complexity

“…Emx2 (empty spiracles homeobox 2) is a transcription factor bearing multiple functions in neuron development, progression and survival, its expression was undetectable in GBM patient derived cultures [ 74 ]. Overexpression of Emx2 in U87MG and T98G cell lines and five GBM cultures from patients, in which Emx2 was selectively activated in only the tumor cells without effect the health cells and was TetON controlled by doxycycline, caused the expansion of the cells arrested for proliferation, significant alteration on the expression of genes related with mitogenic and RTK signaling, and the genes controlling early G1 checkpoint in five GBM patient cultures, and caused the cultures collapsed within 7–8 days after treatment.…”

“…Overexpression of Emx2 in U87MG and T98G cell lines and five GBM cultures from patients, in which Emx2 was selectively activated in only the tumor cells without effect the health cells and was TetON controlled by doxycycline, caused the expansion of the cells arrested for proliferation, significant alteration on the expression of genes related with mitogenic and RTK signaling, and the genes controlling early G1 checkpoint in five GBM patient cultures, and caused the cultures collapsed within 7–8 days after treatment. By restricting Emx2 overexpression ( Emx2 overexpression is highly toxic to neurons) in the tumor cells in xenograft mice, the antioncogenic activity of Emx2 was evidence [ 74 ].…”