Hypoxia and defective apoptosis drive genomic instability and tumorigenesis

  1. Deirdre A. Nelson1,4,9,
  2. Ting-Ting Tan2,4,9,
  3. Arnold B. Rabson2,5,6,7,8,
  4. Diana Anderson2,4,
  5. Kurt Degenhardt3,4, and
  6. Eileen White1,2,3,4,5,8,10
  1. 1Howard Hughes Medical Institute, 2Center for Advanced Biotechnology and Medicine, and 3Department of Molecular Biology and Biochemistry, 4Rutgers University, Piscataway, New Jersey 08854, USA; 5Department of Molecular Genetics and Microbiology, and 6Department of Pathology, 7University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 8Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA

Abstract

Genomic instability is a hallmark of cancer development and progression, and characterizing the stresses that create and the mechanisms by which cells respond to genomic perturbations is essential. Here we demonstrate that antiapoptotic BCL-2 family proteins promoted tumor formation of transformed baby mouse kidney (BMK) epithelial cells by antagonizing BAX- and BAK-dependent apoptosis. Cell death in vivo correlated with hypoxia and induction of PUMA (p53 up-regulated modulator of apoptosis). Strikingly, carcinomas formed by transformed BMK cells in which apoptosis was blocked by aberrant BCL-2 family protein function displayed prevalent, highly polyploid, tumor giant cells. Examination of the transformed BMK cells in vivo revealed aberrant metaphases and ploidy changes in tumors as early as 9 d after implantation, which progressed in magnitude during the tumorigenic process. An in vitro ischemia system mimicked the tumor microenvironment, and gain of BCL-2 or loss of BAX and BAK was sufficient to confer resistance to apoptosis and to allow for accumulation of polyploid cells in vitro. These data suggest that in vivo, even in cells in which p53 function is compromised, apoptosis is an essential response to hypoxia and ischemia in the tumor microenvironment and that abrogation of this response allows the survival of cells with abnormal genomes and promotes tumorigenesis.

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Footnotes

  • Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1204904.

  • 9 These authors contributed equally to this work.

  • 10 Corresponding author. E-MAIL ewhite{at}cabm.rutgers.edu; FAX (732) 235-5795.

    • Accepted July 6, 2004.
    • Received March 19, 2004.
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