Hypoxia-Inducible Factors Regulate Tumorigenic Capacity of Glioma Stem Cells

By Zhizhong Li, S. Bao, Qiulian Wu, Hui Wang, C. Eyler, S. Sathornsumetee, Q. Shi, Yiting Cao, J. Lathia, R. McLendon and 2 more. Cancer Cell, 2009

1,318 citations recorded by the source corpus.

Summary Glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs). As hypoxia regulates angiogenesis, we examined hypoxic responses in GSCs. We now demonstrate that hypoxia-inducible factor HIF2α and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to nonstem tumor cells and normal neural progenitors. In tumor specimens, HIF2α co-localizes with cancer stem cell markers. Targeting HIFs in GSCs inhibits self-renewal, proliferation and survival in vitro, and attenuates tumor initiation potential of GSCs in vivo. Analysis of a molecular database reveals that HIF2A expression correlates with poor glioma patient survival. Our results demonstrate that GSCs differentially respond to hypoxia with distinct HIF induction patterns and HIF2α may represent a promising target for anti-glioblastoma therapies. Significance Recent evidence supports the presence of cancer stem cell populations that contribute to tumor progression through preferential resistance to radiation and chemotherapy, and promotion of tumor angiogenesis, invasion, and metastasis. Therefore, the elucidation of molecular regulators of cancer stem cells may translate into improved anti-neoplastic therapies. Our work demonstrates that cancer stem cells derived from glioblastomas differentially respond to hypoxia with a distinct induction of HIF2α. We find that HIFs are critical to cancer stem cell maintenance and angiogenic drive, and that expression of HIF2α is significantly associated with poor glioma patient survival. These data further suggest that anti-angiogenic therapies can be designed to target cancer stem cell specific molecules involved in neoangiogenesis, including HIF2α and its regulated factors.

Subfields: Cancer Research, Genetics, Oncology

View Paper: https://www.semanticscholar.org/paper/184ad24bbd19411baa7fdd12ed723e453d00b76f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Genetics

In Oncology

Citations in the corpus

Integrin alpha 6 regulates glioblastoma stem cells (2010, methodology): “To evaluate GSC expression of integrin a6, GSCs were derived from human specimens amplified in vivo as previously described (Bao et al., 2006a, 2006b, 2008; Li et al., 2009).”
Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions (2023, background): “Hypoxia is known to promote and maintain CSC phenotypes.(61) CSCs are thought to have the potential to form tumor that will develop into cancer, especially when they metastasize with the cancer and will give rise to novel sources of cancer.”
Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. (2016, methodology): “YC-1 is thought to inhibit HIF-1 activity by preventing its interaction with the p300 co-activator (Li et al., 2008), i.e., the same mechanism used by the endogenous FIH enzyme.”
Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1α (2009, background): “The presence of HIFs has been associated with poor outcome in a variety of different neoplasms (Birner et al., 2000; Aebersold et al., 2001; Semenza, 2003; Shimogai et al., 2008; Li et al., 2009).”
Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma (2010, background): “Experimental depletion of HIFs in glioma CSCs inhibits self-renewal and survival in vitro and tumour initiation potential in vivo”
Cancer stem cells in glioblastoma (2015, background): “Common pathways activated in CSCs include Notch, BMP, NF-κB, and Wnt signaling (Li et al. 2009a; Day et al. 2013; Rheinbay et al. 2013; Lubanska et al. 2014; Yan et al. 2014).”
Oxygen in stem cell biology: a critical component of the stem cell niche. (2010, background): “…mechanisms and stem cell signaling that the convergence of these two pathways that was described initially in ESCs (Adelman et al., 1999), HSCs (Cipolleschi et al., 1993), NSCs (Panchision, 2009), and CSCs (Li et al., 2009) has now further been expanded to include iPSCs (Yoshida 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”
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).”