The embryonic stem cell microenvironment inhibits mouse glioma cell proliferation by regulating the PI3K/AKT pathway

Abstract

Background: Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system, accounting for 48.6% of malignant tumors. The current standard treatment plan includes the widest range of safe surgical resection, supplemented by local brain radiotherapy and temozolomide concurrent chemotherapy; this can cause serious side effects. Even so, the median survival time of GBM patients is only 8 months, and the 5-year survival rate is only 5.5%. It is imminent to find new treatments.Early studies have shown that chicken and zebrafish embryos can reprogram cancer cells into a nontumorigenic phenotype through the embryonic microenvironment. However, the effect of embryonic stem cell microenvironment on GBM and its possible mechanism are not clear.Methods: In this study, the glioblastoma cell line, U118, in the brain was investigated. There were four experimental groups: GB, GE, GA and GT. U118 cells were harvested after culturing for 72 hours. Cell proliferation, apoptosis, reactive oxygen species (ROS) were examined using vasculogenic mimicry assays, quantitative real-time polymerase chain reaction (QRT-PCR), western blotting (WB) and flow cytometry.The differences in the biological function of U118 cells and the PI3K/protein kinase B (AKT) signaling pathway were compared between the groups.Results: Compared with the GB control group, the GE co-culture group and GT chemotherapy group showed reduced cell proliferation, increased apoptosis, increased ROS, as well as decreased or inhibited vasculogenic mimicry. Expressions of cyclin B1 and cyclin D1 were also notably reduced, while that of Bax, Bcl-2, p53, Caspase-3, GSK-3β, p21, and p27 were significantly increased. Moreover, the expression of PI3K, AKT, and mTOR were markedly decreased, whereas expression of PTEN increased considerably.Also, the expression of positive regulatory factors significantly increased, however negative regulatory factors decreased in the GA group compared to the GE group. Conclusions:The ESC microenvironment reverses glioma malignancy, partially via inhibition of the PI3K signaling pathway. Our study may have a significant impact and important clinical implications for cell therapy in the treatment of glioma.

Angiopep-2-Modified Carboxymethyl Chitosan-Based pH/Reduction Dual-Stimuli-Responsive Nanogels for Enhanced Targeting Glioblastoma

“…4 Meanwhile, the side effects of radiotherapy are relatively serious, which will affect the quality of life of patients. 5 Chemotherapy is a popular and feasible method to treat GBM. Nevertheless, the existence of blood−brain barrier (BBB), which is highly selective for permeability, hinders the effective delivery of chemotherapeutics.…”

“…However, the strong infiltration of GBM and unclear tumor boundaries lead to incomplete surgical resection and easy recurrence . Meanwhile, the side effects of radiotherapy are relatively serious, which will affect the quality of life of patients . Chemotherapy is a popular and feasible method to treat GBM.…”

Human embryonic stem cells exert antitumor effects on prostate cancer cells in a co-culture microenvironment

“…The great potential of ESCs in biomedical applications lies in their ability to maintain developmental stability and differentiate into various tissues and cells ( 29 – 31 ). With the further exploration of ESCs, several studies have found that the malignant phenotype of tumor cells is reversed in the ESC microenvironment ( 17 , 19 ). In contrast, differentiated ESCs can contribute to the malignant phenotype of tumor cells ( 32 ).…”

“…This difference has led to an increased interest in the role of ESCs in cancer ( 17 ). Researchers found that ESCs can play a role similar to that of the early embryonic microenvironment and demonstrated that glioma cell proliferation was significantly inhibited by direct contact with murine ESCs ( 19 ). In particular, pretreatment of the microenvironment with hESCs can inhibit the aggressive or tumorigenic phenotype of melanoma cells ( 20 , 21 ), while the maximal inhibitory effects of human ESCs (hESCs) on melanoma cells can be achieved through direct cell-to-cell contact ( 22 , 23 ).…”

Cell-Based Therapy for the Treatment of Glioblastoma: An Update from Preclinical to Clinical Studies

“…He et al used ESCs to simulate the microenvironment of embryos and determined that their ability to lessen the degree of malignancy is due to downregulation of the P13K pathway. The study proved that the ESCs’ microenvironment could inhibit the PI3K pathway to promote apoptosis and thus inhibit GB proliferation [ 160 ].…”