Nature Publishing Group, publisher of Nature, and other science journals and reference works
Nature
my account e-alerts subscribe register
   
Wednesday 24 May 2017
Journal Home
Current Issue
AOP
Archive
Download PDF
References
Export citation
Export references
Send to a friend
More articles like this

Letters to Nature
Nature 379, 88 - 91 (04 January 1996); doi:10.1038/379088a0

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

Thomas G. Graeber*, Cynthia Osmanian*, Tyler Jacks, David E. Housman, Cameron J. Koch§, Scott W. Lowe & Amato J. Giaccia*

* Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305, USA
Department of Biology, Center for Cancer Research, and Howard Hughes Medical Institute, Massachusetts Institute of Technology,Cambridge, Massachusetts 02139, USA
§ Radiation Oncology, University of Pennsylvania, Philadelphia,Pennsylvania 19104, USA
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA
To whom correspondence should be addressed

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.

------------------

References

1. Bellamy, C. O. C., Malcomson, R. D. G., Harrison, D. J. & Wyllie, A. H. Semin. Cancer Biol. 6, 3−16 (1995). | Article | PubMed | ISI | ChemPort |
2. Thompson, C. B. Science 267, 1456−1462 (1995). | PubMed | ISI | ChemPort |
3. Harrington, E. A., Fanidi, A. & Evan, G. I. Curr. Opin. Genet. Dev. 4, 120−129 (1994). | Article | PubMed | ChemPort |
4. Wyllie, A. H. Curr. Opin. Genet. Dev. 5, 97−104 (1995). | Article | PubMed | ChemPort |
5. Symonds, H. et al. Cell 78, 703−711 (1994). | Article | PubMed | ISI | ChemPort |
6. Deng, C., Zhang, P., Harper, J. W., Elledge, S. J. & Leder, P. Cell 82, 675−684 (1995). | Article | PubMed | ISI | ChemPort |
7. Thomlinson, R. H. & Gray, L. H. Br. J. Cancer 9, 539−549 (1955). | PubMed | ISI | ChemPort |
8. Vaupel, P. W. & Hockel, M. in Tumor Oxygenation (eds Vaupel, P. W., Kelleher, D. K. & Gunderoth, M.) 219−232 (Gustav Fischer, Stuttgart, 1995). | ChemPort |
9. Hockel, M., Vorndran, B., Schlenger, K., Baussmann, E. & Knapstein, P. G. Gynecol. Oncol. 51, 141−149 (1993). | PubMed | ChemPort |
10. Littlewood, T. D., Hancock, D. C., Danielian, P. S., Parker, M. G. & Evan, G. I. Nucleic Acids Res. 23, 1686−1690 (1995). | PubMed | ISI | ChemPort |
11. Lane D. P., Lu, X., Hupp, T. & Hall, P. A. Phil. Trans. R. Soc.B 345, 277−280 (1994). | ChemPort |
12. Graeber, T. G. et al. Molec. cell. Biol. 14, 6264−6277 (1994). | PubMed | ChemPort |
13. Lowe, S. W. et al. Science 266, 807−810 (1994). | PubMed | ISI | ChemPort |
14. Lord, E. M., Harwell, L. & Koch, C. J. Cancer Res. 53, 5721−5726 (1993). | PubMed | ISI | ChemPort |
15. Bishop, J. M. Science 235, 305−311 (1987). | PubMed | ISI | ChemPort |
16. Harrington, E. A., Bennett, M. R., Fanidi, A. & Evan, G. I. EMBO J. 13, 3286−3295 (1994). | PubMed | ISI | ChemPort |
17. Lowe, S. W., Ruley, H. E., Jacks, T. & Housman, D. E. Cell 74, 957−967 (1993). | Article | PubMed | ISI | ChemPort |
18. Bardeesy, N., Beckwith, J. B. & Pelletier, J. Cancer Res. 55, 215−219 (1995). | PubMed | ISI | ChemPort |
19. Baker, S. J. et al. Cancer Res. 50, 7717−7722 (1990). | PubMed | ISI | ChemPort |
20. Sinicrope, F. A. et al. Cancer Res. 55, 237−241 (1995). | PubMed | ISI | ChemPort |
21. Bedi, A. et al. Cancer Res. 55, 1811−1816 (1995). | PubMed | ISI | ChemPort |
22. Lotem, J. & Sachs, L. Cell Growth. Differ. 4, 41−47 (1993). | PubMed | ISI | ChemPort |
23. Lowe, S. W. Curr. Opin. Oncol. (in the press).
24. Hickman, J. A., Potten, C. S., Merritt, A. J. & Fisher, T. C. Phil. Trans. R. Soc. B 345, 319−325 (1994). | PubMed | ChemPort |
25. Ziegler, A. et al. Nature 372, 773−776 (1994). | Article | PubMed | ISI | ChemPort |
26. Greenblatt, M. S., Bennett, W. P., Hollstein, M. & Harris, C. C. Cancer Res. 54, 4855−4878 (1994). | PubMed | ISI | ChemPort |
27. Hockenbery, D., Nunez, G., Milliman, C., Schreiber, R. D. & Korsmeyer, S. J. Nature 348, 334−336 (1990). | Article | PubMed | ISI | ChemPort |
28. Lowe, S. W., Jacks, T., Housman, D. E. & Ruley, H. E. Proc. natn. Acad. Sci. U.S.A. 91, 2026−2030 (1994). | ChemPort |
29. Dranoff, G. et al. Proc. natn. Acad. Sci. U.S.A. 90, 3539−3543 (1993). | ChemPort |
30. Pear, W., Nolan, G. P., Scott, M. L. & Baltimore, D. Proc. natn. Acad. Sci. U.S.A. 90, 8392−8396 (1993). | ChemPort |



© 1996 Nature Publishing Group
Privacy Policy