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Cancer stem-like cells can be induced through dedifferentiation under hypoxic conditions in glioma, hepatoma and lung cancer.

ABSTRACT: Traditional studies have shown that transcription factors, including SOX-2, OCT-4, KLF-4, Nanog and Lin-28A, contribute to the dedifferentiation and reprogramming process in normal tissues. Hypoxia is a physiological phenomenon that exists in tumors and promotes the expression of SOX-2, OCT-4, KLF-4, Nanog and Lin-28A. Therefore, an interesting question is whether hypoxia as a stimulating factor promotes the process of dedifferentiation and induces the formation of cancer stem-like cells. Studies have shown that OCT-4 and Nanog overexpression induced the formation of cancer stem cell-like cells through dedifferentiation and enhanced malignancy in lung adenocarcinoma, and reprogramming SOX-2 in pancreatic cancer cells also promoted the dedifferentiation process. Therefore, we investigated this phenomenon in glioma, lung cancer and hepatoma cells and found that the transcription factors mentioned above were highly expressed under hypoxic conditions and induced the formation of spheres, which exhibited asymmetric division and cell cycle arrest. The dedifferentiation process induced by hypoxia highlights a new pattern of cancer development and recurrence, demonstrating that all kinds of cancer cells and the hypoxic microenvironment should be taken into consideration when developing tumor therapies.

SUBMITTER: Wang P

PROVIDER: S-EPMC5253691 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Cancer stem-like cells can be induced through dedifferentiation under hypoxic conditions in glioma, hepatoma and lung cancer.

Wang Pan P Wan Wen-Wu WW Xiong Shuang-Long SL Feng Hua H Wu Nan N Wu Nan N

Cell death discovery 20170123

Traditional studies have shown that transcription factors, including SOX-2, OCT-4, KLF-4, Nanog and Lin-28A, contribute to the dedifferentiation and reprogramming process in normal tissues. Hypoxia is a physiological phenomenon that exists in tumors and promotes the expression of SOX-2, OCT-4, KLF-4, Nanog and Lin-28A. Therefore, an interesting question is whether hypoxia as a stimulating factor promotes the process of dedifferentiation and induces the formation of cancer stem-like cells. Studie ...[more]

PMID: 28179999

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Project description:Objective: Our previous study showed that glioma stem-like cells could be induced to undergo dedifferentiation under hypoxic conditions, but the mechanism requires further study. HIF1α and HIF2α are the main molecules involved in the response to hypoxia, and Sox2, as a retroelement, plays an important role in the formation of induced pluripotent stem cells, especially in hypoxic microenvironments. Therefore, we performed a series of experiments to verify whether HIF1α, HIF2α and Sox2 regulated glioma cell dedifferentiation under hypoxic conditions. Materials and methods: Sphere formation by single glioma cells was observed, and CD133 and CD15 expression was compared between the normoxic and hypoxic groups. HIF1α, HIF2α, and Sox2 expression was detected using the CGGA database, and the correlation among HIF1α, HIF2α and Sox2 levels was analyzed. We knocked out HIF1α, HIF2α and Sox2 in glioma cells and cultured them under hypoxic conditions to detect CD133 and CD15 expression. The above cells were implanted into mouse brains to analyze tumor volume and survival time. Results: New spheres were formed from single glioma cells in 1% O2, but no spheres were formed in 21% O2. The cells cultured in 1% O2 highly expressed CD133 and CD15 and had a lower apoptosis rate. The CGGA database showed HIF1α and HIF2α expression in glioma. Knocking out HIF1α or HIF2α led to a decrease in CD133 and CD15 expression and inhibited sphere formation under hypoxic conditions. Moreover, tumor volume and weight decreased after HIF1α or HIF2α knockout with the same temozolomide treatment. Sox2 was also highly expressed in glioma, and there was a positive correlation between the HIF1α/HIF2α and Sox2 expression levels. Sox2 was expressed at lower levels after HIF1α or HIF2α was knocked out. Then, Sox2 was knocked out, and we found that CD133 and CD15 expression was decreased. Moreover, a lower sphere formation rate, higher apoptosis rate, lower tumor formation rate and longer survival time after temozolomide treatment were detected in the Sox2 knockout cells. Conclusion: In a hypoxic microenvironment, the HIF1α/HIF2α-Sox2 network induced the formation of glioma stem cells through the dedifferentiation of differentiated glioma cells, thus promoting glioma cell chemoresistance. This study demonstrates that both HIF1α and HIF2α, as genes upstream of Sox2, regulate the malignant progression of glioma through dedifferentiation.

Project description:Bone marrow derived human mesenchymal stem cells (hMSCs) have attracted great interest from both bench and clinical researchers because of their pluripotency and ease of expansion ex vivo. However, these cells do finally reach a senescent stage and lose their multipotent potential. Proliferation of these cells is limited up to the time of their senescence, which limits their supply, and they may accumulate chromosomal changes through ex vivo culturing. The safe, rapid expansion of hMSCs is critical for their clinical application. Chromosomal aberration is known as one of the hallmarks of human cancer, and therefore it is important to understand the chromosomal stability and variability of ex vivo expanded hMSCs before they are used widely in clinical applications. In this study, we examined the effects of culturing under ambient (20%) or physiologic (5%) O(2) concentrations on the rate of cell proliferation and on the spontaneous transformation of hMSCs in primary culture and after expansion, because it has been reported that culturing under hypoxic conditions accelerates the propagation of hMSCs. Bone marrow samples were collected from 40 patients involved in clinical research. We found that hypoxic conditions promote cell proliferation more favourably than normoxic conditions. Chromosomal aberrations, including structural instability or aneuploidy, were detected in significantly earlier passages under hypoxic conditions than under normoxic culture conditions, suggesting that amplification of hMSCs in a low-oxygen environment facilitated chromosomal instability. Furthermore, smoothed hazard-function modelling of chromosomal aberrations showed increased hazard after the fourth passage under both sets of culture conditions, and showed a tendency to increase the detection rate of primary karyotypic abnormalities among donors aged 60 years and over. In conclusion, we propose that the continuous monitoring of hMSCs will be required before they are used in therapeutic applications in the clinic, especially when cells are cultured under hypoxic conditions.

Dataset Information

Cancer stem-like cells can be induced through dedifferentiation under hypoxic conditions in glioma, hepatoma and lung cancer.

Publications

Cancer stem-like cells can be induced through dedifferentiation under hypoxic conditions in glioma, hepatoma and lung cancer.

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