Hypoxia and defective apoptosis drive genomic instability and tumorigenesis.
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.
Howard Hughes Medical Institute, Rutgers University, Piscataway, New Jersey 08854, USA.
Deirdre A
DA
Nelson
Ting-Ting
TT
Tan
Arnold B
AB
Rabson
Diana
D
Anderson
Kurt
K
Degenhardt
Eileen
E
White
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D005434:Flow Cytometry; D019254:Genes, bcl-2 / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics / Q000502:physiology*; D000860:Hypoxia / Q000503:physiopathology*; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein