Oligodendrocytes Up-regulate the Invasive Activity of Glioblastoma Cells via the Angiopoietin-2 Signaling Pathway

Abstract

Background/Aim: Glioblastoma (GBM) is one of the most lethal solid cancers due to its highly invasive nature. The malignant potential of GBM cells might be partially regulated by surrounding normal cells, such as oligodendrocytes or fibroblasts. The aim of this study was to examine the interaction between stromal cells and GBM cells. Materials and Methods: Two GBM cell lines were used. The effect of stromal cells, oligodendrocytes or fibroblasts, on the invasive ability of GBM cells was examined by wound-healing assay and invasion assay. Results: Oligodendrocytes, in contrast to fibroblasts, significantly increased the migration and invasive ability of GBM cells. Angiopoietin-2 levels were high in the conditioned medium obtained from oligodendrocytes. Angiopoietin-2 significantly increased the motility of GBM, and the motilitystimulating activity of the oligodendrocytes-derived conditioned medium was significantly decreased by anti-angiopoietin-2neutralizing antibody. Conclusion: Glioma stromal cells, oligodendrocytes, might up-regulate the invasiveness of GBM cells via angiopoietin-2 signaling.Diffuse glioma comprises the majority of primary brain tumors (1, 2). Recently, diffuse gliomas were classified as WHO grade II, III, and Ⅳ, based not only on their growth pattern and behavior, but also on genetic driver mutations in IDH1 and IDH2 genes (3). The current classification is based on the theory that primary glioblastoma (GBM) occurs de novo without the need of a less malignant precursor tumor, whereas secondary GBM arises from a lower-grade diffuse glioma (WHO grade II or III) (4). In spite of the standard multimodal treatments including surgical resection, chemotherapy, and radiotherapy, the median survival time of GBM patients is only around 14.6 months (1, 2). Surgical resection of diffuse gliomas is frequently non-curative because of their highly invasive nature (5). Therefore, a more thorough investigation of the invasive ability of GBM cells is of utmost importance for the discovery of novel therapies to improve the prognosis of patients with diffuse glioma.Tumor development is not only determined by malignant tumor cells themselves, but also by the tumor stroma. Recently, it was reported that tumor progression depends on the interactions between tumor cells and its surrounding tumor stromal cells (6, 7). Oligodendrocytes, fibroblasts, and astrocytes are considered stroma cells for diffuse glioma, especially GBM (8,9). However, the correlation between diffuse glioma cells and its surrounding tumor stroma cells has not been fully clarified. This study aimed to investigate the effect of stromal cells on the invasion of GBM cells and identify factors/signaling pathways that regulate migration and invasiveness of GBM. To the best of our knowledge, this is the first study to show that oligodendrocyte cells might up-regulate the invasive ability of GBM cells via angiopoietin-2 signaling. Materials and MethodsCell culture and cell lines. Two glioblastoma (GBM) cell lines, T98G and U251 were purchased from the J...

Up-regulated cytotrophoblast DOCK4 contributes to over-invasion in placenta accreta spectrum

“…Beyond DOCK 4, our analyses suggested PAS-associated dysregulation of other genes with suspected roles in cell signaling and migration/invasion in the context of cancer, including BST2 ( 36 , 37 ), ANGPT2 ( 38 , 39 ), and IGFBP5 ( 40 ). While the specific roles of these genes in CTBs are not yet understood, these molecules may drive the hyperinvasive state of CTBs in PAS placentas and will be an interesting area of investigation for future studies.…”

Neuroimmunomodulatory Properties of Flavonoids and Derivates: A Potential Action as Adjuvants for the Treatment of Glioblastoma

“…They are responsible for the regular homeostasis of the CNS, supporting neurons through neurotransmitter precursor release. Besides, they regulate metabolism, release diverse chemical substances, contribute to functional hyperemia and regulate blood-brain [31,34]. Surrounding GBM cells, astrocytes respond with a reactive phenotype characterized by GFAP overexpression, and the crosstalk to other components of the environment is poorly understood [35].…”

“…Oligodendrocytes are considered as stroma cells for diffuse glioma, especially GBM. There is an up-regulation of the invasive activity of GBM cells via the Angiopoietin-2 (Ang-2) signaling pathway [34]. Also, oligodendrocyte progenitor cells (OPCs) "in the border niche" may induce stemness and chemo-radioresistance in GBM cells, providing a supportive function for promoting GBM aggressiveness.…”

Ang2-Targeted Combination Therapy for Cancer Treatment

“…Ang-2 is highly expressed in glioblastoma and is involved in a series of processes such as glioma development, invasion, prognosis and treatment resistance (56,(59)(60)(61). Rhythm gene BMAL1 (brain and muscle Arnt like 1) is considered to be a tumor-promoting factor in glioma and plays a key role in the proliferation and migration of glioma cells (59).…”

“…Some studies have shown that the edema of glioblastoma can be alleviated by dexamethasone, and it is suggested that dexamethasone may alleviate brain edema and slow down the growth of gliomas by inhibiting the expression of Ang2 (63). In oligodendroglioma, it was found that under hypoxia, Insulin Gene Enhancer Protein (ISL2) induces angiogenesis by enhancing the expression of Ang2 to promote the growth, malignant transformation and invasion of oligodendroglioma (13,56). These studies suggest that blocking Ang2-induced angiogenesis through targeted inhibition of ISL2 may be one of the effective strategies for the treatment of oligodendroglioma in the future (13).…”