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Hypoxia inducible factors in cancer stem cells

Journal

BRITISH JOURNAL OF CANCER
Volume 102, Issue 5, Pages 789-795

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/sj.bjc.6605551

Keywords

HIF; hypoxia; cancer stem cell

Categories

Funding

  1. Childhood Brain Tumor Foundation
  2. Pediatric Brain Tumor Foundation of the United States
  3. Accelerate Brain Cancer Cure
  4. Alexander and Margaret Stewart Trust
  5. Brain Tumor Society
  6. Goldhirsh Foundation
  7. NIH [NS047409, NS054276, CA112958, CA116659]
  8. Damon Runyon Cancer Research Foundation
  9. Sidney Kimmel Foundation
  10. National Brain Tumor Society
  11. American Brain Tumor Association Basic Research Fellowship
  12. National Service Research Award [NCI F32 CA142159]
  13. Cleveland Clinic Foundation Tissue Procurement Service

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Oxygen is an essential regulator of cellular metabolism, survival, and proliferation. Cellular responses to oxygen levels are monitored, in part, by the transcriptional activity of the hypoxia inducible factors (HIFs). Under hypoxia, HIFs regulate a variety of pro-angiogenic and pro-glycolysis pathways. In solid cancers, regions of hypoxia are commonly present throughout the tissue because of the chaotic vascular architecture and regions of necrosis. In these regions, the hypoxic state fluctuates in a spatial and temporal manner. Transient hypoxic cycling causes an increase in the activity of the HIF proteins above what is typical for non-pathologic tissue. The extent of hypoxia strongly correlates to poor patient survival, therapeutic resistance and an aggressive tumour phenotype, but the full contribution of hypoxia and the HIFs to tumour biology is an area of active investigation. Recent reports link resistance to conventional therapies and the metastatic potential to a stem-like tumour population, termed cancer stem cells (CSCs). We and others have shown that within brain tumours CSCs reside in two niches, a perivascular location and the surrounding necrotic tissue. Restricted oxygen conditions increase the CSC fraction and promote acquisition of a stem-like state. Cancer stem cells are critically dependant on the HIFs for survival, self-renewal, and tumour growth. These observations and those from normal stem cell biology provide a new mechanistic explanation for the contribution of hypoxia to malignancy. Further, the presence of hypoxia in tumours may present challenges for therapy because of the promotion of CSC phenotypes even upon successful killing of CSCs. The current experimental evidence suggests that CSCs are plastic cell states governed by microenvironmental conditions, such as hypoxia, that may be critical for the development of new therapies targeted to disrupt the microenvironment. British Journal of Cancer (2010) 102, 789-795. doi: 10.1038/sj.bjc.6605551 www.bjcancer.com Published online 26 January 2010 (C) 2010 Cancer Research UK

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