Creation of human tumour cells with defined genetic elements (original) (raw)

Nature volume 400, pages 464–468 (1999)Cite this article

Abstract

During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogenes1,2. However, similar experiments with human cells have consistently failed to yield tumorigenic transformants3,4,5, indicating a fundamental difference in the biology of human and rodent cells. The few reported successes in the creation of human tumour cells have depended on the use of chemical or physical agents to achieve immortalization6, the selection of rare, spontaneously arising immortalized cells7,8,9,10, or the use of an entire viral genome11. We show here that the ectopic expression of the telomerase catalytic subunit (hTERT)12 in combination with two oncogenes (the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras) results in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrate that disruption of the intracellular pathways regulated by large-T, oncogenic ras and telomerase suffices to create a human tumor cell.

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Acknowledgements

We thank M. Fleming for interpretation of tumour histology, J. Smith for the gift of early passage BJ fibroblasts, and S. Dessain, B. Elenbaas, D. Fruman, P. Steiner, S. Stewart and the members of Weinberg laboratory for helpful discussions and review of the manuscript. This work was supported in part by Merck and Co. (R.A.W.), the US NCI (R.A.W., A.S.L.), a Damon Runyon–Walter Winchell Cancer Research Foundation Postdoctoral Fellowship (W.C.H.), and a Human Frontiers Postdoctoral Fellowship (R.L.B.). C.M.C. is a Whitehead Scholar; W.C.H. is a Herman and Margaret Sokol postdoctoral fellow. R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.

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Author notes

  1. William C. Hahn and Christopher M. Counter: These authors contributed equally to this work.

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, 9 Cambridge Center
    William C. Hahn, Ante S. Lundberg, Roderick L. Beijersbergen, Mary W. Brooks & Robert A. Weinberg
  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02142, Massachusetts, USA
    William C. Hahn, Ante S. Lundberg, Roderick L. Beijersbergen, Mary W. Brooks & Robert A. Weinberg
  3. Department of Adult Oncology, Departments of Medicine, Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, 02115, Massachusetts, USA
    William C. Hahn & Ante S. Lundberg
  4. Department of Pharmacology and Cancer Biology, Department of Radiation Oncology, Box 3813
    Christopher M. Counter
  5. Duke University Medical Center, Durham, 27710, North Carolina, USA
    Christopher M. Counter

Authors

  1. William C. Hahn
  2. Christopher M. Counter
  3. Ante S. Lundberg
  4. Roderick L. Beijersbergen
  5. Mary W. Brooks
  6. Robert A. Weinberg

Corresponding author

Correspondence toRobert A. Weinberg.

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Hahn, W., Counter, C., Lundberg, A. et al. Creation of human tumour cells with defined genetic elements.Nature 400, 464–468 (1999). https://doi.org/10.1038/22780

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