Hypoxia and defective apoptosis drive genomic instability and tumorigenesis

Genes Dev. 2004 Sep 1;18(17):2095-107. doi: 10.1101/gad.1204904. Epub 2004 Aug 16.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins
  • Blotting, Western
  • Cell Line
  • Disease Models, Animal
  • Flow Cytometry
  • Genes, bcl-2 / genetics*
  • Genomic Instability / genetics
  • Genomic Instability / physiology*
  • Hypoxia / physiopathology*
  • Immunohistochemistry
  • Membrane Proteins / antagonists & inhibitors
  • Mice
  • Mice, Nude
  • Microscopy, Confocal
  • Neoplasms / etiology
  • Neoplasms / genetics*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2*
  • Transfection
  • Tumor Suppressor Proteins / metabolism
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein

Substances

  • Apoptosis Regulatory Proteins
  • Bak1 protein, mouse
  • Bax protein, mouse
  • Membrane Proteins
  • PUMA protein, mouse
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein