Hypoxia Enhances Stemness of Cancer Stem Cells in Glioblastoma: An In Vitro Study

Abstract

Objective: To investigate the relationship between hypoxia and in vitro “stemness” of cancer stem cells (CSCs). Methods: U87 cells, U251 cells and primary glioma cells (n=3) experienced hypoxia. Transmission electron microscopy was done to detect the ultrastructure of these cancer cells; MTT assay to detect the cell growth; flow cytometry to detect cell cycle and CD133 expression; Transwell chamber assay was carried out to detect the cell migration; colony-forming assay to detect the colony-forming efficiency; real-time quantitative PCR and Western blot were carried out to detect the mRNA and protein expression of markers of stem cells and their differentiation, respectively. Results: Hypoxia maintained the undifferentiated state of primary glioma cells, slowed down the growth of glioma cells which were in a relatively quiescent stage, increased the colony forming efficiency and migration of glioma cells, and elevated the expression of markers of stem cells, but the expression of markers for stem cell differentiation was reduced after hypoxia treatment. Conclusion: Hypoxia may induce the "dedifferentiation" of differentiated glioma cells which then acquire the stemness.

Hypoxia promotes stem-like properties of laryngeal cancer cell lines by increasing the CD133+ stem cell fraction

“…3E and F). These findings were in agreement with previous studies (12)(13)(14), indicating that the influence of hypoxia on the stem-like property may be exerted through changes in the expression of these stem cell transcriptional factors.…”

“…Hypoxia is an inherent feature of solid tumors, and when the tumor volume reaches 2 ml, the oxygen tension could be close to 0 mmHg (18). Recent studies show that hypoxia, as a critical component of the tumor microenvironment, can directly regulate the stem-like properties of CSCs in ways such as selfrenewal, differentiation, migration and invasion, colony and sphere formation, and therapeutic resistance (12)(13)(14)19). In this study, we investigated whether hypoxia is able to regulate the stem-like biological properties of laryngeal cancer cells and discussed the possible mechanisms involved.…”

“…Ovarian cancer cells under hypoxia upgrade their stem-like properties through the upregulation of stemness-related factors and behave more aggressively when returned to a higher oxygen environment (13). Similarly, hypoxia maintains the undifferentiated state of primary glioma cells, slows down their growth to a relatively quiescent stage, increases their colony forming efficiency and migration, and elevates the expression of stem cell markers (14).…”

Quantitative Profiling of Chromatome Dynamics Reveals a Novel Role for HP1BP3 in Hypoxia-induced Oncogenesis

“…Indeed, the hypoxic tumor microenvironment appears to be a common driver of cancer evolution-all solid tumors are subjected to hypoxia stress at some point during development as they increase in size without an immediate increase in oxygen supply. Emerging evidence also suggests that hypoxia contributes to the development of cancer stem cells that exhibit enhanced capacity for self-renewal (6). Together, these data indicate a critical role for hypoxia-sensitive molecular pathways in promoting cancer progression that it may be possible to target with novel therapies in order to disrupt tumor growth (7).…”

Therapeutic Potential of Glioblastoma Stem Cells

“…On the other hand Notch pathway is essential for hypoxiamediated maintenance of GSCs, either depletion of HIF-1a or inactivation of Notch signaling partly inhibited the hypoxiamediated maintenance of GSCs. Li et al [40] showed that hypoxic environment increased the expression of CD133 and nestin which are markers of CSCs, but reduced the proportion of cells positive for GFAP, a marker for differentiation of stem cells and Li an colleagues concluded that hypoxia could de-differentiate the differentiated glioma cells and promote the acquisition of stemness in these cells. But these studies are in vitro and in vivo studies are required to show the specific mechanism for hypoxia and treatment resistance and future studies will be aimed to identify the target for the treatment of glioma.…”