The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype

Heddleston, John M.; Li, Zhizhong; McLendon, Roger E.; Hjelmeland, Anita B.; Rich, Jeremy

doi:10.4161/cc.8.20.9701

Cited by 698 publications

(729 citation statements)

References 72 publications

(92 reference statements)

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“…Initially described in cultured neuroblastoma and breast cancer cells and in breast tumor specimens, hypoxia can push tumor cells towards an immature, stem cell-like phenotype (Jögi et al 2002;Helczynska et al 2003). The phenomenon has recently also been observed in glioma (Heddleston et al 2009) suggesting that the dedifferentiating effect of hypoxia could be general and not restricted to specific tumor forms. These observations have potentially direct clinical impact, since at least in neuroblastoma and breast carcinoma, immature stages of differentiation correlate to aggressive tumor behavior and unfavorable outcome.…”

Section: Hypoxia and Tumor Cell Differentiationmentioning

confidence: 77%

“…By pushing HIF-2α + tumor stem cells toward a more mature, tumor bulk-like phenotype by interfering with the expression or activity of HIF-2, the tumor stem cell pool as well as the bulk of tumor cells, targeted by existing, efficient treatment protocols, would be reduced in numbers. The demonstration that both neuroblastoma and glioma stem/initiating cells differentiate in vivo when HIF-2α is knocked down Heddleston et al 2009;Li et al 2009) can be seen as proof of principle. Diminished HIF-2α activity also leads to reduced VEGF expression in these two tumor stem cell models, and as would be anticipated, neuroblastoma and glioma tumors with reduced HIF-2α expression are highly necrotic Li et al 2009;Heddleston et al 2009), suggesting that targeting HIF-2α will result in both an anti-angiogenic effect and a reduction of the tumor stem cell pool.…”

Section: Hif-2α and The Pseudo-hypoxic Phenotype --Targets For Tumormentioning

confidence: 99%

“…The demonstration that both neuroblastoma and glioma stem/initiating cells differentiate in vivo when HIF-2α is knocked down Heddleston et al 2009;Li et al 2009) can be seen as proof of principle. Diminished HIF-2α activity also leads to reduced VEGF expression in these two tumor stem cell models, and as would be anticipated, neuroblastoma and glioma tumors with reduced HIF-2α expression are highly necrotic Li et al 2009;Heddleston et al 2009), suggesting that targeting HIF-2α will result in both an anti-angiogenic effect and a reduction of the tumor stem cell pool. As high HIF-2α protein levels associate with disseminated disease, targeting of HIF-2α or the HIF-2α-driven pseudo-hypoxic phenotype might also affect tumor spread and transition into advanced clinical stages.…”

Section: Hif-2α and The Pseudo-hypoxic Phenotype --Targets For Tumormentioning

confidence: 99%

“…In glioma, cell populations enriched for tumor stem cell properties have high HIF-2α protein levels, and, as in neuroblastoma, has been suggested to be a marker of glioma stem cells. In addition, downregulation of HIF-2α in such cells results in decreased tumor initiating capacity and glial differentiation Heddleston et al 2009). In line with these findings are the observations that HIF-2α protein expression correlates to breast cancer specific death and distant metastasis, the latter process most likely dependent on the presence of cells with tumor stem cell properties.…”

Section: Hif-2α and Tumor Initiating/stem Cellsmentioning

confidence: 99%

“…Importantly, and the reason for the focus on HIF-2α in this review, HIF-1α and HIF-2α are differently regulated in tumors such as neuroblastoma, breast cancer, non-small cell lung carcinoma (NSCLC) and glioma and seem to have different impact on tumor behavior and patient outcome in these tumors (Holmquist-Mengelbier et al 2006;Helczynska et al 2008;Heddleston et al 2009;Kim et al 2009b;Li et al 2009;Noguera et al 2009). …”

Section: Introductionmentioning

confidence: 99%

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The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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Section: Hypoxia and Tumor Cell Differentiationmentioning

confidence: 77%

Section: Hif-2α and The Pseudo-hypoxic Phenotype --Targets For Tumormentioning

confidence: 99%

Section: Hif-2α and The Pseudo-hypoxic Phenotype --Targets For Tumormentioning

confidence: 99%

Section: Hif-2α and Tumor Initiating/stem Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

Pietras

Johnsson

Påhlman

2010

Current Topics in Microbiology and Immunology

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CNSCancers

Graeme

2010

Burger's Medicinal Chemistry and Drug Discovery

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CNS tumors represent a diverse collection of tumor types driven by a range of signaling inputs that often generate highly aggressive and at the same time heterogeneous tumor types. The effect of these tumors is particularly dramatic and impacts on children as well as adults. Malignant CNS tumors are characterized by being highly heterogeneous, aggressive, and frequently invasive, leading to poor overall patient survival times. As CNS tumors present within the nervous system, there are particular challenges in the development of effective molecular‐targeted therapies in dealing not only with the aggressive nature of these tumors and their ability to evade treatment but also, particularly, with maintaining normal neuronal and brain functions. Compounding this is the need to deliver systemically small molecules or other agents such as vaccines and for immunotherapy approaches to confront the complexity of the relationship between the nervous system and the immune system. Research to find effective treatments for CNS tumors is being facilitated by two key inputs both of which are reviewed in this chapter; first, a much greater understanding of tumor pathobiology and the potential role of developmental signaling pathways and tumor stem‐like cells, and by the development of animal models that more adequately represent endpoints measurable in the clinic. Together, these advances should assist in the selection of better targets and the optimization of better compounds to progress into clinical trials.

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Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

et al. 2019

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Hepatocellular carcinoma ( HCC ) is the third leading cause of cancer death worldwide. HCC treatment is hindered by the frequent emergence of chemoresistance to the multikinase inhibitor sorafenib, which has been related to the presence of cancer stem cells ( CSC s) that self‐renew and often escape therapy. The key metabolic sensor AMP ‐activated kinase ( AMPK ) has recently been recognized as a tumour growth regulator. In this study, we aimed to elucidate the role of AMPK in the development of a stem cell phenotype in HCC cells. To this end, we enriched the CSC population in HCC cell lines that showed increased expression of drug resistance ( ALDH 1A1, ABCB 1A) and stem cell ( CD 133, Nanog, Oct4, alpha fetoprotein) markers and demonstrated their stemness phenotype. These cells were refractory to sorafenib‐induced cell death. We report that sorafenib‐resistant cells had lower levels of total and phosphorylated AMPK as well as its downstream substrate, ACC , compared with the parental cells. Interestingly, AMPK knockdown with si RNA or inhibition with dorsomorphin increased the expression of stem cell markers in parental cells and blocked sorafenib‐induced cell death. Conversely, the upregulation of AMPK , either by transfection or by pharmacological activation with A‐769662, decreased the expression of ALDH 1A1, ABCB 1A, CD 133, Nanog, Oct4, and alpha fetoprotein, and restored sensitivity to sorafenib. Analysis of the underlying mechanism points to hypoxia‐inducible factor HIF ‐1α as a regulator of stemness. In vivo studies in a xenograft mouse model demonstrated that stem‐like cells have greater tumourigenic capacity. AMPK activation reduced xenograft tumour growth and decreased the expression of stem cell markers. Taken together, these results indicate that AMPK may serve as a novel target to overcome chemoresistance in HCC .

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The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype

Cited by 698 publications

References 72 publications

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

The HIF-2α-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization

CNSCancers

Targeting AMP‐activated kinase impacts hepatocellular cancer stem cells induced by long‐term treatment with sorafenib

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