Skip to main content
SpringerLink
Log in

Hypoxia and Hypoxia Inducible Factors in Cancer Stem Cell Maintenance

  • Chapter
  • First Online:
Book cover Diverse Effects of Hypoxia on Tumor Progression

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 345))

Abstract

Hypoxia promotes tumor progression through multiple mechanisms including modifying angiogenesis, metabolism switch and invasion. Hypoxia inducible factors (HIFs), particularly HIF1α and HIF2α, are key mediators in cancer hypoxia response and high expression levels of HIFs correlate with a poor prognosis in various tumor types. Cancer stem cells (CSCs), also known as cancer initiating cells or tumor propagation cells, are neoplastic cells that could self-renewal, differentiate as well as initiate tumor growth in vivo. Cancer stem cells are believed to be the key drivers in tumor growth and therapy resistance. Hypoxia has been shown to help maintain multiple normal stem cell population but its roles in cancer stem cells were largely unknown. Our group and other researchers recently identified that hypoxia is also a critical microenvironmental factor in regulating cancer stem cells’ self-renewal, partially by enhancing the activity of stem cell factors like Oct4, c-Myc and Nanog. The effects of hypoxia on cancer stem cells seem to be primarily mediated by HIFs, particularly HIF2α. HIF2α is highly expressed in cancer stem cells in gliomas and neuroblastomas and loss of HIF2α leads to significant decrease in cancer stem cell proliferation and self-renewal. These findings illustrated a new mechanism through which oxygen tension and microenvironment influences cancer development. Targeting hypoxia niches may therefore improve therapy efficacy by eliminating cancer stem cell population.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Acker T, Diez-Juan A et al (2005) Genetic evidence for a tumor suppressor role of HIF-2alpha. Cancer Cell 8(2):131–141

    Article  PubMed  CAS  Google Scholar 

  • Al-Hajj M, Wicha MS et al (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983–3988

    Article  PubMed  CAS  Google Scholar 

  • Axelson H, Fredlund E et al (2005) Hypoxia-induced dedifferentiation of tumor cells–a mechanism behind heterogeneity and aggressiveness of solid tumors. Semin Cell Dev Biol 16(4–5):554–563

    PubMed  CAS  Google Scholar 

  • Bangoura G, Liu ZS et al (2007) Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma. World J Gastroenterol 13(23):3176–3182

    PubMed  CAS  Google Scholar 

  • Bao S, Wu Q et al (2006a) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444(7120):756–760

    Article  PubMed  CAS  Google Scholar 

  • Bao S, Wu Q et al (2006b) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848

    Article  PubMed  CAS  Google Scholar 

  • Bertout JA, Majmundar AJ et al (2009) HIF2alpha inhibition promotes p53 pathway activity, tumor cell death, and radiation responses. Proc Natl Acad Sci USA 106(34):14391–14396

    Article  PubMed  CAS  Google Scholar 

  • Bertout JA, Patel SA et al (2008) The impact of O2 availability on human cancer. Nat Rev Cancer 8(12):967–975

    Article  PubMed  CAS  Google Scholar 

  • Bolos V, Blanco M et al (2009) Notch signalling in cancer stem cells. Clin Transl Oncol 11(1):11–19

    Article  PubMed  CAS  Google Scholar 

  • Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737

    Article  PubMed  CAS  Google Scholar 

  • Calabrese C, Poppleton H et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11(1):69–82

    Article  PubMed  CAS  Google Scholar 

  • Carroll VA, Ashcroft M (2006) Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. Cancer Res 66(12):6264–6270

    Article  PubMed  CAS  Google Scholar 

  • Chow DC, Wenning LA et al (2001) Modeling pO(2) distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models. Biophys J 81(2):685–696

    Article  PubMed  CAS  Google Scholar 

  • Clement V, Sanchez P et al (2007) HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17(2):165–172

    Article  PubMed  CAS  Google Scholar 

  • Conrad PW, Freeman TL et al (1999) EPAS1 trans-activation during hypoxia requires p42/p44 MAPK. J Biol Chem 274(47):33709–33713

    Article  PubMed  CAS  Google Scholar 

  • Covello KL, Kehler J et al (2006) HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 20(5):557–570

    Article  PubMed  CAS  Google Scholar 

  • Danet GH, Pan Y et al (2003) Expansion of human SCID-repopulating cells under hypoxic conditions. J Clin Invest 112(1):126–135

    PubMed  CAS  Google Scholar 

  • Ema M, Taya S et al (1997) A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA 94(9):4273–4278

    Article  PubMed  CAS  Google Scholar 

  • Ezashi T, Das P et al (2005) Low O2 tensions and the prevention of differentiation of hES cells. Proc Natl Acad Sci USA 102(13):4783–4788

    Article  PubMed  CAS  Google Scholar 

  • Giatromanolaki A, Koukourakis MI et al (2001) Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J Cancer 85(6):881–890

    Article  PubMed  CAS  Google Scholar 

  • Gilbertson RJ, Rich JN (2007) Making a tumour’s bed: glioblastoma stem cells and the vascular niche. Nat Rev Cancer 7(10):733–736

    Article  PubMed  CAS  Google Scholar 

  • Gordan JD, Bertout JA et al (2007) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11(4):335–347

    Article  PubMed  CAS  Google Scholar 

  • Gustafsson MV, Zheng X et al (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9(5):617–628

    Article  PubMed  CAS  Google Scholar 

  • Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38–47

    Article  PubMed  CAS  Google Scholar 

  • Heddleston JM, Li Z et al (2009) The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. Cell Cycle 8(20):3274–3284

    Article  PubMed  CAS  Google Scholar 

  • Helczynska K, Larsson AM et al (2008) Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. Cancer Res 68(22):9212–9220

    Article  PubMed  CAS  Google Scholar 

  • Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93(4):266–276

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann AC, Mori R et al (2008) High expression of HIF1a is a predictor of clinical outcome in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA, VEGF, and bFGF. Neoplasia 10(7):674–679

    PubMed  Google Scholar 

  • Holmquist-Mengelbier L, Fredlund E et al (2006) Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype. Cancer Cell 10(5):413–423

    Article  PubMed  CAS  Google Scholar 

  • Ivan M, Kondo K et al (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292(5516):464–468

    Article  PubMed  CAS  Google Scholar 

  • Jaakkola P, Mole DR et al (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292(5516):468–472

    Article  PubMed  CAS  Google Scholar 

  • Kaur B, Khwaja FW et al (2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 7(2):134–153

    Article  PubMed  CAS  Google Scholar 

  • Kiel MJ, Morrison SJ (2008) Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 8(4):290–301

    Article  PubMed  CAS  Google Scholar 

  • Kimura H, Braun RD et al (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56(23):5522–5528

    PubMed  CAS  Google Scholar 

  • Li Z, Bao S et al (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15(6):501–513

    Article  PubMed  CAS  Google Scholar 

  • Makino Y, Cao R et al (2001) Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression. Nature 414(6863):550–554

    Article  PubMed  CAS  Google Scholar 

  • Malanchi I, Peinado H et al (2008) Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 452(7187):650–653

    Article  PubMed  CAS  Google Scholar 

  • Maxwell PH, Wiesener MS et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399(6733):271–275

    Article  PubMed  CAS  Google Scholar 

  • O’Brien CA, Pollett A et al (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110

    Article  PubMed  Google Scholar 

  • Perry JM, Li L (2007) Disrupting the stem cell niche: good seeds in bad soil. Cell 129(6):1045–1047

    Article  PubMed  CAS  Google Scholar 

  • Pietras A, Hansford LM et al (2009) HIF-2alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells. Proc Natl Acad Sci USA 106(39):16805–16810

    Article  PubMed  CAS  Google Scholar 

  • Pouyssegur J, Dayan F et al (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441(7092):437–443

    Article  PubMed  CAS  Google Scholar 

  • Reya T, Morrison SJ et al (2001) Stem cells, cancer, and cancer stem cells. Nature 414(6859):105–111

    Article  PubMed  CAS  Google Scholar 

  • Schwarz G (1909) Ueber Desensibilisierung gegen röntgen- und radiumstrahlen. Munchener Medizinische Wochenschrift 24:1–2

    Google Scholar 

  • Shen Q, Wang Y et al (2008) Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3(3):289–300

    Article  PubMed  CAS  Google Scholar 

  • Singh SK, Clarke ID et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828

    PubMed  CAS  Google Scholar 

  • Soeda A, Park M et al (2009) Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28(45):3949–3959

    Article  PubMed  CAS  Google Scholar 

  • Studer L, Csete M et al (2000) Enhanced proliferation, survival, and dopaminergic differentiation of CNS precursors in lowered oxygen. J Neurosci 20(19):7377–7383

    PubMed  CAS  Google Scholar 

  • Tang W, Zeve D et al (2008) White fat progenitor cells reside in the adipose vasculature. Science 322(5901):583–586

    Article  PubMed  CAS  Google Scholar 

  • Tavazoie M, Van der Veken L et al (2008) A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3(3):279–288

    Article  PubMed  CAS  Google Scholar 

  • Vaupel P, Mayer A (2007) Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 26(2):225–239

    Article  PubMed  CAS  Google Scholar 

  • Wang V, Davis DA et al (2005) Differential gene up-regulation by hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha in HEK293T cells. Cancer Res 65(8):3299–3306

    PubMed  CAS  Google Scholar 

  • Warburg O (1956) On the origin of cancer cells. Science 123(3191):309–314

    Article  PubMed  CAS  Google Scholar 

  • Wion D, Christen T et al (2009) PO(2) matters in stem cell culture. Cell Stem Cell 5(3):242–243

    Article  PubMed  CAS  Google Scholar 

  • Yang MH, Wu MZ et al (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10(3):295–305

    Article  PubMed  CAS  Google Scholar 

  • Yoshida S, Sukeno M et al (2007) A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 317(5845):1722–1726

    Article  PubMed  CAS  Google Scholar 

  • Yoshida Y, Takahashi K et al (2009) Hypoxia enhances the generation of induced pluripotent stem cells. Cell Stem Cell 5(3):237–241

    Article  PubMed  CAS  Google Scholar 

  • Zhang J, Li L (2008) Stem cell niche: microenvironment and beyond. J Biol Chem 283(15):9499–9503

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Guo W et al (2008) Human colon cancer stem cells locate in hypoxic niche. J Clin Oncol, 2008 ASCO Annual meeting proceedings 26(15S):Abstract 22209

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Duke University Medical Center, Durham, NC, 27710, USA

    Zhizhong Li

  2. Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 44195, USA

    Jeremy N. Rich

Authors
  1. Zhizhong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremy N. Rich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeremy N. Rich .

Editor information

Editors and Affiliations

  1. Medicine, University of Pennsylvania School of, Philadelphia, 19104-6160, Pennsylvania, USA

    M. Celeste Simon

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Li, Z., Rich, J.N. (2010). Hypoxia and Hypoxia Inducible Factors in Cancer Stem Cell Maintenance. In: Simon, M. (eds) Diverse Effects of Hypoxia on Tumor Progression. Current Topics in Microbiology and Immunology, vol 345. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2010_75

Download citation

Publish with us

Policies and ethics

Search

Navigation