Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours


APOPTOSIS is a genetically encoded programme of cell death that can be activated under physiological conditions1,2 and may be an important safeguard against tumour development3–6. Regions of low oxygen (hypoxia) and necrosis are common features of solid tumours7,8.Here we report that hypoxia induces apoptosis in oncogenically transformed cells and that further genetic alterations, such as loss of the p53 tumour-suppressor gene or over-expression of the apoptosis-inhibitor protein Bcl-2, substantially reduce hypoxia-induced cell death. Hypoxia also selects for cells with defects in apoptosis, because small numbers of transformed cells lacking p53 overtake similar cells expressing wild-type p53 when treated with hypoxia. Furthermore, highly apoptotic regions strongly correlate with hypoxic regions in transplanted tumours expressing wild-type p53, whereas little apoptosis occurs in hypoxic regions of p53-deficient tumours. We propose that hypoxia provides a physiological selective pressure in tumours for the expansion of variants that have lost their apoptotic potential, and in particular for cells acquiring p53mutations.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1

    Bellamy, C. O. C., Malcomson, R. D. G., Harrison, D. J. & Wyllie, A. H. Semin. Cancer Biol. 6, 3–16 (1995).

    CAS  Article  Google Scholar 

  2. 2

    Thompson, C. B. Science 267, 1456–1462 (1995).

    ADS  CAS  Article  Google Scholar 

  3. 3

    Harrington, E. A., Fanidi, A. & Evan, G. I. Curr. Opin. Genet. Dev. 4, 120–129 (1994).

    CAS  Article  Google Scholar 

  4. 4

    Wyllie, A. H. Curr. Opin. Genet. Dev. 5, 97–104 (1995).

    CAS  Article  Google Scholar 

  5. 5

    Symonds, H. et al. Cell 78, 703–711 (1994).

    CAS  Article  Google Scholar 

  6. 6

    Deng, C., Zhang, P., Harper, J. W., Elledge, S. J. & Leder, P. Cell 82, 675–684 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Thomlinson, R. H. & Gray, L. H. Br. J. Cancer 9, 539–549 (1955).

    CAS  Article  Google Scholar 

  8. 8

    Vaupel, P. W. & Hockel, M. in Tumor Oxygenation (eds Vaupel, P. W., Kelleher, D. K. & Gunderoth, M.) 219–232 (Gustav Fischer, Stuttgart, 1995).

    Google Scholar 

  9. 9

    Hockel, M., Vorndran, B., Schlenger, K., Baussmann, E. & Knapstein, P. G. Gynecol. Oncol. 51, 141–149 (1993).

    CAS  Article  Google Scholar 

  10. 10

    Littlewood, T. D., Hancock, D. C., Danielian, P. S., Parker, M. G. & Evan, G. I. Nucleic Acids Res. 23, 1686–1690 (1995).

    CAS  Article  Google Scholar 

  11. 11

    Lane D. P., Lu, X., Hupp, T. & Hall, P. A. Phil. Trans. R. Soc.B 345, 277–280 (1994).

    CAS  Article  Google Scholar 

  12. 12

    Graeber, T. G. et al. Molec. cell. Biol. 14, 6264–6277 (1994).

    CAS  Article  Google Scholar 

  13. 13

    Lowe, S. W. et al. Science 266, 807–810 (1994).

    ADS  CAS  Article  Google Scholar 

  14. 14

    Lord, E. M., Harwell, L. & Koch, C. J. Cancer Res. 53, 5721–5726 (1993).

    CAS  PubMed  Google Scholar 

  15. 15

    Bishop, J. M. Science 235, 305–311 (1987).

    ADS  CAS  Article  Google Scholar 

  16. 16

    Harrington, E. A., Bennett, M. R., Fanidi, A. & Evan, G. I. EMBO J. 13, 3286–3295 (1994).

    CAS  Article  Google Scholar 

  17. 17

    Lowe, S. W., Ruley, H. E., Jacks, T. & Housman, D. E. Cell 74, 957–967 (1993).

    CAS  Article  Google Scholar 

  18. 18

    Bardeesy, N., Beckwith, J. B. & Pelletier, J. Cancer Res. 55, 215–219 (1995).

    CAS  PubMed  Google Scholar 

  19. 19

    Baker, S. J. et al. Cancer Res. 50, 7717–7722 (1990).

    CAS  Google Scholar 

  20. 20

    Sinicrope, F. A. et al. Cancer Res. 55, 237–241 (1995).

    CAS  PubMed  Google Scholar 

  21. 21

    Bedi, A. et al. Cancer Res. 55, 1811–1816 (1995).

    CAS  PubMed  Google Scholar 

  22. 22

    Lotem, J. & Sachs, L. Cell Growth. Differ. 4, 41–47 (1993).

    CAS  PubMed  Google Scholar 

  23. 23

    Lowe, S. W. Curr. Opin. Oncol. (in the press).

  24. 24

    Hickman, J. A., Potten, C. S., Merritt, A. J. & Fisher, T. C. Phil. Trans. R. Soc. B 345, 319–325 (1994).

    ADS  CAS  Article  Google Scholar 

  25. 25

    Ziegler, A. et al. Nature 372, 773–776 (1994).

    ADS  CAS  Article  Google Scholar 

  26. 26

    Greenblatt, M. S., Bennett, W. P., Hollstein, M. & Harris, C. C. Cancer Res. 54, 4855–4878 (1994).

    CAS  Google Scholar 

  27. 27

    Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R. D. & Korsmeyer, S. J. Nature 348, 334–336 (1990).

    ADS  CAS  Article  Google Scholar 

  28. 28

    Lowe, S. W., Jacks, T., Housman, D. E. & Ruley, H. E. Proc. natn. Acad. Sci. U.S.A. 91, 2026–2030 (1994).

    ADS  CAS  Article  Google Scholar 

  29. 29

    Dranoff, G. et al. Proc. natn. Acad. Sci. U.S.A. 90, 3539–3543 (1993).

    ADS  CAS  Article  Google Scholar 

  30. 30

    Pear, W., Nolan, G. P., Scott, M. L. & Baltimore, D. Proc. natn. Acad. Sci. U.S.A. 90, 8392–8396 (1993).

    ADS  CAS  Article  Google Scholar 

Download references

Author information



Rights and permissions

Reprints and Permissions

About this article

Cite this article

Graeber, T., Osmanian, C., Jacks, T. et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379, 88–91 (1996). https://doi.org/10.1038/379088a0

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing