Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Jul 1;19(7):887-896.
doi: 10.1093/neuonc/now258.

Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells

Nicole Colwell  1 , Mioara Larion  1 , Amber J Giles  1 , Ashlee N Seldomridge  1 , Saman Sizdahkhani  1 , Mark R Gilbert  1 , Deric M Park  1
Affiliations
Review

Hypoxia in the glioblastoma microenvironment: shaping the phenotype of cancer stem-like cells

Nicole Colwell et al. Neuro Oncol. .

Abstract

Glioblastoma is the most common and aggressive malignant primary brain tumor. Cellular heterogeneity is a characteristic feature of the disease and contributes to the difficulty in formulating effective therapies. Glioma stem-like cells (GSCs) have been identified as a subpopulation of tumor cells that are thought to be largely responsible for resistance to treatment. Intratumoral hypoxia contributes to maintenance of the GSCs by supporting the critical stem cell traits of multipotency, self-renewal, and tumorigenicity. This review highlights the interaction of GSCs with the hypoxic tumor microenvironment, exploring the mechanisms underlying the contribution of GSCs to tumor vessel dynamics, immune modulation, and metabolic alteration.

Keywords: cancer stem cell; glioblastoma; hypoxia; tumor metabolism.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Tumor vessel dynamics. Mechanisms of tumor-associated blood vessel formation. HIF-mediated VEGF is secreted by GSCs during angiogenesis, resulting in endothelial tip cell formation and sprouting of vessels. HIF promotes Notch signaling by stabilizing the liberated intracellular domain (ICD). Bone marrow–derived endothelial progenitor cells (EPCs) are recruited by GSC-secreted SDF-1. CSL = CBF1/suppresor of Hairless/Lag1; NO = nitric oxide.
Fig. 2
Fig. 2
Immune modulation. Effects of HIF stabilization are cell type specific, including increased TAM expression of PD-L1 and increased CD4+ T-cell secretion of interferon-gamma (IFN-γ). NANOG-mediated secretion of TGF-β by GSCs supports local immunosuppressive cells and promotes stem cell phenotype in an autocrine fashion.
Fig. 3
Fig. 3
Metabolic alterations. Cells respond to hypoxic environment by upregulating glucose transporter (GLUT)1/3 transporters, which facilitates glucose influx. HIF activation upregulates glycolytic enzymes and inhibits oxidative phosphorylation. HIF decreases pyruvate entry into the TCA cycle via upregulation of PDK1 and PDK1-mediated deactivation of PDH. Increased glycolysis leads to lactate accumulation; however, MCT facilitates its extracellular transport. HK = hexokinase; PDK1 = pyruvate dehydrogenase kinase 1; DHAP = dihydroxyacetone phosphate.
See this image and copyright information in PMC

References

    1. Virchow RL. Cellular Pathology. 1859 special ed. London: John Churchill; 1978:204–207.
    1. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science. 1988;241(4861):58–62. - PubMed
    1. Caceres-Cortes J, Mindeni M, Patersoni B, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:17. - PubMed
    1. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63(18):5821–5828. - PubMed
    1. Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells can arise from pediatric brain tumors. Proc Natl Acad Sci U S A. 2003;100(25):15178–15183. - PMC - PubMed