• Journal of Microbiology and Biotechnology
• /
• v.28 no.1
• /
• pp.165-174
• /
• 2018

Glioblastoma multiforme is the most lethal malignant brain tumor. Despite many intensive studies, the prognosis of glioblastoma multiforme is currently very poor, with a median overall survival duration of 14 months and 2-year survival rates of less than 10%. Although viral infections have been emphasized as potential cofactors, their influences on pathways that support glioblastoma progression are not known. Some previous studies indicated that human Kaposi's sarcoma-associated herpesvirus (KSHV) was detected in healthy brains, and its microRNA was also detected in glioblastoma patients' plasma. However, a direct link between KSHV infection and glioblastoma is currently not known. In this study, we infected glioblastoma cells and glioma stem-like cells (GSCs) with KSHV to establish an in vitro cell model for KSHV-infected glioblastoma cells and glioma stem-like cells in order to identify virologic outcomes that overlap with markers of aggressive disease. Latently KSHV-infected glioblastoma cells and GSCs were successfully established. Additionally, using these cell models, we found that KSHV infection modulates the proliferation of glioma stem-like cells.

• Asian Pacific Journal of Cancer Prevention
• /
• v.17 no.3
• /
• pp.1553-1564
• /
• 2016

Identification of novel therapeutics in glioblastoma remains crucial due to the devastating and infiltrative capacity of this malignancy. The current study was aimed to appraise effect of arsenic trioxide (ATO) in U87MG cells. The results demonstrated that ATO induced apoptosis and impeded proliferation of U87MG cells in a dose-dependent manner and also inhibited classical NF-${\kappa}B$ signaling pathway. ATO further upregulated expression of Bax as an important proapoptotic target of NF-${\kappa}B$ and also inhibited mRNA expression of survivin, c-Myc and hTERT and suppressed telomerase activity. Moreover, ATO significantly increased adhesion of U87MG cells and also diminished transcription of NF-${\kappa}B$ down-stream targets involved in cell migration and invasion, including cathepsin B, uPA, MMP-2, MMP-9 and MMP-14 and suppressed proteolytic activity of cathepsin B, MMP-2 and MMP-9, demonstrating a possible mechanism of ATO effect on a well-known signaling in glioblastoma dissemination. Taken together, here we suggest that ATO inhibits survival and invasion of U87MG cells possibly through NF-${\kappa}B$-mediated inhibition of survivin and telomerase activity and NF-${\kappa}B$-dependent suppression of cathepsin B, MMP-2 and MMP-9.

• Journal of Korean Neurosurgical Society
• /
• v.66 no.4
• /
• pp.356-381
• /
• 2023

Although immunotherapy has been broadly successful in the treatment of hematologic malignancies and a subset of solid tumors, its clinical outcomes for glioblastoma are still inadequate. The results could be due to neuroanatomical structures such as the blood-brain-barrier, antigenic heterogeneity, and the highly immunosuppressive microenvironment of glioblastomas. The antitumor efficacy of endogenously activated effector cells induced by peptide or dendritic cell vaccines in particular has been insufficient to control tumors. Effector cells, such as T cells and natural killer (NK) cells can be expanded rapidly ex vivo and transferred to patients. The identification of neoantigens derived from tumor-specific mutations is expanding the list of tumor-specific antigens for glioblastoma. Moreover, recent advances in gene-editing technologies enable the effector cells to not only have multiple biological functionalities, such as cytokine production, multiple antigen recognition, and increased cell trafficking, but also relieve the immunosuppressive nature of the glioblastoma microenvironment by blocking immune inhibitory molecules, which together improve their cytotoxicity, persistence, and safety. Allogeneic chimeric antigen receptor (CAR) T cells edited to reduce graft-versus-host disease and allorejection, or induced pluripotent stem cell-derived NK cells expressing CARs that use NK-specific signaling domain can be a good candidate for off-the-shelf products of glioblastoma immunotherapy. We here discuss current progress and future directions for T cell and NK cell therapy in glioblastoma.

• BMB Reports
• /
• v.51 no.10
• /
• pp.481-483
• /
• 2018

Glioblastoma (GBM) is the most common and aggressive form of human adult brain malignancy. The identification of the cell of origin harboring cancer-driver mutations is the fundamental issue for understanding the nature of GBM and developing the effective therapeutic target. It has been a long-term hypothesis that neural stem cells in the subventricular zone (SVZ) might be the origin-of-cells in human glioblastoma since they are known to have life-long proliferative activity and acquire somatic mutations. However, the cell of origin for GBM remains controversial due to lack of direct evidence thereof in human GBM. Our recent study using various sequencing techniques in triple matched samples such as tumor-free SVZ, tumor, and normal tissues from human patients identified the clonal relationship of driver mutations between GBM and tumor-free SVZ harboring neural stem cells (NSCs). Tumor-free SVZ tissue away from the tumor contained low-level GBM driver mutations (as low as 1% allelic frequency) that were found in the dominant clones in its matching tumors. Moreover, via single-cell sequencing and microdissection, it was discovered that astrocyte-like NSCs accumulating driver mutations evolved into GBM with clonal expansion. Furthermore, mutagenesis of cancer-driving genes of NSCs in mice leads to migration of mutant cells from SVZ to distant brain and development of high-grade glioma through the aberrant growth of oligodendrocyte precursor lineage. Altogether, the present study provides the first direct evidence that NSCs in human SVZ is the cell of origin that develops the driver mutations of GBM.

• Molecules and Cells
• /
• v.39 no.8
• /
• pp.619-624
• /
• 2016

Glioblastoma stem cells (GBM-SCs) are believed to be a subpopulation within all glioblastoma (GBM) cells that are in large part responsible for tumor growth and the high grade of therapeutic resistance that is so characteristic of GBM. MicroRNAs (miR) have been implicated in regulating the expression of oncogenes and tumor suppressor genes in cancer stem cells, including GBM-SCs, and they are a potential target for cancer therapy. In the current study, miR-203 expression was reduced in $CD133^+$ GBM-SCs derived from six human GBM biopsies. MicroRNA-203 transfected GBM-SCs had reduced capacity for self-renewal in the cell sphere assay and increased expression of glial and neuronal differentiation markers. In addition, a reduced proliferation rate and an increased rate of apoptosis were observed. Therefore, miR-203 has the potential to reduce features of stemness, specifically in GBM-SCs, and is a logical target for GBM gene therapy.

• BMB Reports
• /
• v.44 no.3
• /
• pp.158-164
• /
• 2011

Gliomas are the most frequently occurring primary malignancies in the central nervous system, and glioblastoma multiforme (GBM) is the most common and most aggressive of these tumors. Despite vigorous basic and clinical studies over past decades, the median survival of patients with this disease remains at about one year. Recent studies have suggested that GBMs contain a subpopulation of tumor cells that displays stem cell characteristics and could therefore be responsible for in vivo tumor growth. We will summarize the major oncogenic pathways abnormally regulated in gliomas, and review the recent findings from mouse models that our laboratory as well as others have developed for the study of GBM. The concept of cancer stem cells in GBM and their potential therapeutic importance will also be discussed.

• Molecules and Cells
• /
• v.28 no.1
• /
• pp.7-12
• /
• 2009

Gliomas, much like other cancers, are composed of a heterogeneous mix of neoplastic and non-neoplastic cells that include both native and recruited cells. There is extensive diversity among the tumor cells, with differing capacity for In vitro and in vivo growth, a property intimately linked to the cell's differentiation status. Those cells that are undifferentiated, self-renewing, with the capacity for developing tumors (tumorigenic) cells are designated by some as cancer stem cells, because of the stem-like properties. These cells may be a critical therapeutic target. However the exact identity and cell(s) of origin of the socalled glioma cancer stem cell remain elusive. Here we review the current understanding of glioma cancer stem cell biology.

• Molecules and Cells
• /
• v.42 no.2
• /
• pp.135-142
• /
• 2019

OCT4, also known as POU5F1 (POU domain class 5 transcription factor 1), is a transcription factor that acts as a master regulator of pluripotency in embryonic stem cells and is one of the reprogramming factors required for generating induced pluripotent stem cells. The human OCT4 encodes three isoforms, OCT4A, OCT4B, and OCT4B1, which are generated by alternative splicing. Currently, the functions and expression patterns of OCT4B remain largely unknown in malignancies, especially in human glioblastomas. Here, we demonstrated the function of OCT4B in human glioblastomas. Among the isoform of OCT4B, OCT4B-190 ($OCT4B^{19kDa}$) was highly expressed in human glioblastoma stem cells and glioblastoma cells and was mainly detected in the cytoplasm rather than the nucleus. Overexpression of $OCT4B^{19kDa}$ promoted colony formation of glioblastoma cells when grown in soft agar culture conditions. Clinical data analysis revealed that patients with gliomas that expressed OCT4B at high levels had a poorer prognosis than patients with gliomas that expressed OCT4B at low levels. Thus, $OCT4B^{19kDa}$ may play a crucial role in regulating cancer cell survival and adaption in a rigid environment.

• Korean Journal of Food Science and Technology
• /
• v.54 no.1
• /
• pp.28-34
• /
• 2022

Glioblastoma is the most common primary malignant brain tumor and has an extremely poor prognosis. Glioblastoma stem cells (GSCs) contribute to tumor initiation, recurrence, and resistance to therapy, and are thus a key therapeutic target. The peel of Citrus unshiu Markovich has been used in traditional medicine in East Asia to treat various diseases. In this study, we investigated the anticancer activity and molecular mechanism of the chloroform extract of this natural product (CECU) in U87MG GSCs. The results show that CECU inhibited the proliferation, tumorsphere formation, and migration of U87MG GSCs by causing cell cycle arrest at the G0/G1 phase and apoptosis. In addition, CECU downregulated key cancer stemness regulators, including CD133, Oct4, Nanog, integrin α6, ALDH1A1, and STAT3 signaling in U87MG GSCs. Furthermore, CECU significantly suppressed in vivo tumor growth of U87MG GSCs in a chorioallantoic membrane model. Therefore, CECU can be utilized as a natural medicine for the prevention and treatment of glioblastoma.

• Journal of Life Science
• /
• v.17 no.8 s.88
• /
• pp.1039-1045
• /
• 2007

Glioblastoma multiforme (GBM) is the most frequently occurring brain cancer. Although the existence of cancer stem cells (CSCs) in GBM has been established, there is little evidence to explain the link between CSCs and chemoresistance. In this study, we investigated that only a few cells of A172 and established GBM2 survived after 1,3-bis(2chloroethyl)-1-nitrosourea (BiCNU) exposures and these sur-vived cells resist the subsequent BiCNU treatment. In addition, these BiCNU-resistant small pop-ulations derived from GBM cells increased the phosphorylations of Erk and Akt and highly expressed CD133 stem cell surface marker. Furthermore, we observed that the BiCNU-resistant cancer cells de-rived from GBM have grown tumors when transplanted into severe combined immuno-deficient (SCID) mouse brain. These results demonstrate that BiCNU-resistant subpopulation cells derived from GBM have cancer stem-like cell properties. Therefore, it may provide provide further evidence that CSCs in GBM have chemotherapeutic drug resistance.