The Hypoxic Microenvironment Maintains Glioblastoma Stem Cells and Promotes Reprogramming towards a Cancer Stem Cell Phenotype

By John M. Heddleston, Zhizhong Li, Anita B. Hjelmeland, Jeremy N. Rich. Cell Cycle, 2009

784 citations recorded by the source corpus.

Glioblastomas are highly lethal cancers that contain cellular hierarchies with self-renewing cancer stem cells that can propagate tumors in secondary transplant assays. The potential significance of cancer stem cells in cancer biology has been demonstrated by studies showing contributions to therapeutic resistance, angiogenesis, and tumor dispersal. We recently reported that physiologic oxygen levels differentially induce hypoxia inducible factor-2α (HIF2α) levels in cancer stem cells. HIF1α functioned in proliferation and survival of all cancer cells but also was activated in normal neural progenitors suggesting a potentially restricted therapeutic index while HIF2α was essential in only in cancer stem cells and was not expressed by normal neural progenitors demonstrating HIF2α is a cancer stem cell specific target. We now extend these studies to examine the role of hypoxia in regulating tumor cell plasticity. We find that hypoxia promotes the self-renewal capability of the stem and non-stem population as well as promoting a more stem-like phenotype in the non-stem population with increased neurosphere formation as well as upregulation of important stem cell factors, such as OCT4, NANOG, and c-MYC. The importance of HIF2α was further supported as forced expression of non-degradable HIF2α induced a cancer stem cell marker and augmented the tumorigenic potential of the non-stem population. This novel finding may indicate a specific role of HIF2α in promoting glioma tumorigenesis. The unexpected plasticity of the non-stem glioma population and the stem-like phenotype emphasizes the importance of developing therapeutic strategies targeting the microenvironmental influence on the tumor in addition to cancer stem cells.

Subfields: Cancer Research, Genetics, Oncology

View Paper: https://www.semanticscholar.org/paper/181b165460b8e01d2dad252fdaa1e9b978e2bccb

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Citations in the corpus

Cancer stem cells: current status and evolving complexities. (2012, background): “HIF2a, induced as a cellular response to a hypoxic microenvironment, has been implicated in the maintenance of CSCs in glioblastoma and may promote the interconversion of nonstem (CD133 ) to CSC-like cells (Heddleston et al., 2009; Li et al., 2009).”
Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging (2011, background): “Recently the Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways have been shown to have roles in cancer stem cells, senescence, aging and sensitivity to targeted therapy [203-245].”
Cancer stem cells in glioblastoma (2015, background): “In addition, it is necessary to consider that therapeutic resistancemechanismsmay not be solely innate but may evolve from exposure to microenvironmental factors such as hypoxia and acidic and metabolic stress (Heddleston et al. 2009; Li et al. 2009b; Hjelmeland et al. 2011; Flavahan et al. 2013; Xi”
Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer (2009, background): “However, hypoxia has been proposed to influence development of both tissue stem cells and cancer stem cells [250, 251].”
Targeting cancer stem cell pathways for cancer therapy (2020, background): “443 HIF-1α regulates the proliferation and fate of CSCs in medulloblastoma and glioblastoma multiforme 444 and activates the NF-κB pathway to promote CSC survival and tumorigenesis.”
Oxygen in stem cell biology: a critical component of the stem cell niche. (2010, background): “Direct evidence for this model was recently provided by Jeremy Rich’s group, who demonstrated that CD133 CSCs from gliomas preferentially expressed HIF-2a and multiple HIF-regulated genes when compared to non-stem tumor cells and normal neural progenitors (Heddleston et al., 2009; Li et al., 2009).”
Integrating diverse genomic data using gene sets (2011, background): “The induction of the glycolytic pathway we have documented in STS patients is likely to represent an adaptive consequence of hypoxic conditions, mediated by genomic alteration and/or expression of hypoxia inducible factors (HIF1A and HIF2A), which have been shown to induce glycolytic genes [18], and”