Hypoxia and hypoxia-inducible factors in neuroblastoma

Påhlman, Sven; Mohlin, Sofie

doi:10.1007/s00441-017-2701-1

Cited by 64 publications

(68 citation statements)

References 34 publications

(61 reference statements)

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“…Hypoxia is a common metabolic stress existing in the tumor microenvironment. Previous studies have showed that hypoxia promotes dedifferentiation of neuroblastoma cells toward a neural crest-like phenotype and favors more aggressive features, which in turn resulting in poor clinical outcome [4][5][6][7] . However, the mechanism by which hypoxia blocks cell differentiation has not been identified.…”

Section: Introductionmentioning

confidence: 99%

Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia

Gruber

Litzenburger

et al. 2020

Cell Death Dis

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Despite the fact that Otto H. Warburg discovered the Warburg effect almost one hundred years ago, why cancer cells waste most of the glucose carbon as lactate remains an enigma. Warburg proposed a connection between the Warburg effect and cell dedifferentiation. Hypoxia is a common tumor microenvironmental stress that induces the Warburg effect and blocks tumor cell differentiation. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma differentiation model, we discovered that hypoxia repressed cell differentiation through reducing cellular acetyl-CoA levels, leading to reduction of global histone acetylation and chromatin accessibility. The metabolic switch triggering this global histone hypoacetylation was the induction of pyruvate dehydrogenase kinases (PDK1 and PDK3). Inhibition of PDKs using dichloroacetate (DCA) restored acetyl-CoA generation and histone acetylation under hypoxia. Knocking down PDK1 induced neuroblastoma cell differentiation, highlighting the critical role of PDK1 in cell fate control. Importantly, acetate or glycerol triacetate (GTA) supplementation restored differentiation markers expression and neuron differentiation under hypoxia. Moreover, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduced chromatin accessibility at RAR/RXR binding sites, which can be restored by acetate supplementation. In addition, hypoxia-induced histone hypermethylation by increasing 2-hydroxyglutarate (2HG) and reducing α-ketoglutarate (αKG). αKG supplementation reduced histone hypermethylation upon hypoxia, but did not restore histone acetylation or differentiation markers expression. Together, these findings suggest that diverting pyruvate flux away from acetyl-CoA generation to lactate production is the key mechanism that Warburg effect drives dedifferentiation and tumorigenesis. We propose that combining differentiation therapy with acetate/GTA supplementation might represent an effective therapy against neuroblastoma.

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Section: Introductionmentioning

confidence: 99%

Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia

Gruber

Litzenburger

et al. 2020

Cell Death Dis

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“…Hypoxia inducible factors HIF-1α and HIF-2α are transcription factors that are stabilized in the presence of low oxygen partial pressure and represent hypoxia key downstream effectors. They account for a significant fraction of the transcriptional control by hypoxia and hypoxia-inducible mRNAs (including those involved in angiogenesis, metabolism and apoptosis) [ 14 , 15 ]. Few studies have performed genome-wide gene expression analysis comparing human bone marrow derived MSCs cultured under atmospheric oxygen partial pressure (20% O 2 ) versus severe hypoxic (0.5% O 2 ) to moderate hypoxic (5% O 2 ) oxygen partial pressures [ 16 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

Comparing atmospheric and hypoxic cultured mesenchymal stem cell transcriptome: implication for stem cell therapies targeting intervertebral discs

Elabd¹,

Ichim

Miller³

et al. 2018

J Transl Med

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BackgroundMesenchymal stem cells (MSCs) represent an attractive avenue for cellular therapies targeting degenerative diseases. MSC in vitro expansion is required in order to obtain therapeutic numbers during the manufacturing process. It is known that culture conditions impact cellular properties and behavior after in vivo transplantation. In this study, we aimed at evaluating the benefit of hypoxic culturing of human bone marrow derived mesenchymal stem cells on cell fitness and whole genome expression and discussed its implication on cellular therapies targeting orthopedic diseases such as chronic lower back pain.MethodsHuman bone marrow mesenchymal stem cells (hBMMSCs) were isolated from fresh human anticoagulated whole bone marrow and were cultured side by side in atmospheric (20% O2) and hypoxic (5% O2) oxygen partial pressure for up to 3 passages. Stem cell fitness was assessed by clonogenic assay, cell surface marker expression and differentiation potential. Whole genome expression was performed by mRNA sequencing. Data from clonogenic assays, cell surface marker by flow cytometry and gene expression by quantitative PCR were analyzed by two-tailed paired Student’s t-test. Data from mRNA sequencing were aligned to hg19 using Tophat-2.0.13 and analyzed using Cufflinks-2.1.1.ResultsHypoxic culturing of hBMMSCs had positive effects on cell fitness, as evidenced by an increased clonogenicity and improved differentiation potential towards adipocyte and chondrocyte lineages. No difference in osteoblast differentiation or in cell surface markers were observed. Only a small subset of genes (34) were identified by mRNA sequencing to be significantly dysregulated by hypoxia. When clustered by biological function, these genes were associated with chondrogenesis and cartilage metabolism, inflammation and immunomodulation, cellular survival, migration and proliferation, vasculogenesis and angiogenesis.ConclusionsHypoxic culturing positively impacted hBMMSCs fitness and transcriptome, potentially improving inherent properties of these cells that are critical for the development of successful cellular therapies. Hypoxic culturing should be considered for the in vitro expansion of hBMMSCs during manufacturing of cellular therapies targeting orthopedic disorders such as lower back pain.

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“…CSCs are known to be more resistant to conventional chemo-and radio-therapy compared to non-CSC populations. Pre-clinical and clinical trials in multiple tumor types have targeted CSCs via surface markers, inhibition of developmental stem cell pathways, or ablation of CSC niches [reviewed in (75)]. In neuroblastoma (NB) a common link between signaling cascades involved in tumorigenesis is hypoxia, and in hypoxic regions of NB, HIF1, and HIF2 have been shown to be expressed in cells with stem-like features (76).…”

Section: Csc Targeted Therapiesmentioning

confidence: 99%

Cancer Stem Cells in Pheochromocytoma and Paraganglioma

et al. 2020

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Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors associated with high cardiovascular morbidity and variable risk of malignancy. The current therapy of choice is surgical resection. Nevertheless, PCCs/PGLs are associated with a lifelong risk of tumor persistence or recurrence. A high rate of germline or somatic mutations in numerous genes has been found in these tumors. For some, the tumorigenic processes are initiated during embryogenesis. Such tumors carry gene mutations leading to pseudohypoxic phenotypes and show more immature characteristics than other chromaffin cell tumors; they are also often multifocal or metastatic and occur at an early age, often during childhood. Cancer stem cells (CSCs) are cells with an inherent ability of self-renewal, de-differentiation, and capacity to initiate and maintain malignant tumor growth. Targeting CSCs to inhibit cancer progression has become an attractive anti-cancer therapeutic strategy. Despite progress for this strategy for solid tumors such as neuroblastoma, brain, breast, and colon cancers, no substantial advance has been made employing similar strategies in PCCs/PGLs. In the current review, we discuss findings related to the identification of normal chromaffin stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs in PCCs/PGLs. Additionally, we examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating especially recurrent and metastatic tumors.

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Hypoxia and hypoxia-inducible factors in neuroblastoma

Cited by 64 publications

References 34 publications

Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia

Acetate supplementation restores chromatin accessibility and promotes tumor cell differentiation under hypoxia

Comparing atmospheric and hypoxic cultured mesenchymal stem cell transcriptome: implication for stem cell therapies targeting intervertebral discs

Cancer Stem Cells in Pheochromocytoma and Paraganglioma

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