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Updated: Aug 9, 2026
Induction and Testing of Hypoxia in Cell Culture
Published on: August 12, 2011
Hypoxia and defective apoptosis drive genomic instability and tumorigenesis
Deirdre A Nelson1, Ting-Ting Tan, Arnold B Rabson
1Howard Hughes Medical Institute, Rutgers University, Piscataway, New Jersey 08854, 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.
Insights
Aberrant BCL-2 proteins promote tumor growth by blocking apoptosis, leading to polyploid giant cells. This genomic instability occurs even with compromised p53, highlighting apoptosis
Area of Science:
- Cancer Biology
- Cellular Stress Response
- Genomics
Background:
- Genomic instability is a key feature of cancer.
- Understanding cellular responses to genomic damage is crucial for cancer research.
Purpose of the Study:
- To investigate the role of antiapoptotic BCL-2 family proteins in tumor formation.
- To characterize the mechanisms by which apoptosis is inhibited in cancer cells.
- To explore the consequences of impaired apoptosis on genomic stability and tumor progression.
Main Methods:
- Utilized transformed baby mouse kidney (BMK) epithelial cells.
- Studied apoptosis regulation by BCL-2 family proteins, BAX, and BAK.
- Examined cellular responses in vivo and in vitro, including hypoxia and ischemia models.
- Analyzed genomic instability, polyploidy, and cell death markers like PUMA (p53 up-regulated modulator of apoptosis).
Main Results:
- Antiapoptotic BCL-2 proteins promoted tumor formation by inhibiting BAX/BAK-dependent apoptosis.
- Tumors exhibited prevalent, highly polyploid giant cells.
- Genomic instability, including aberrant metaphases and polyploidy, was observed early in tumor development.
- In vitro models confirmed that BCL-2 gain or BAX/BAK loss confers apoptosis resistance and polyploidy.
Conclusions:
- Apoptosis is essential for responding to hypoxia and ischemia in the tumor microenvironment, even with compromised p53.
- Abrogation of apoptosis by aberrant BCL-2 proteins allows survival of cells with abnormal genomes.
- Inhibition of apoptosis drives tumorigenesis and the accumulation of polyploid cells.
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