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Brain and testicular tumors in mice with progenitor cells lacking BAX and BAK

Oncogene volume 32, pages 4078–4085 (2013)Cite this article

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Abstract

The proapoptotic BCL-2 family proteins BAX and BAK serve as essential gatekeepers of the intrinsic apoptotic pathway and, when activated, transform into pore-forming homo-oligomers that permeabilize the mitochondrial outer membrane. Deletion of Bax and Bak causes marked resistance to death stimuli in a variety of cell types. Bax−/−Bak−/− mice are predominantly non-viable and survivors exhibit multiple developmental abnormalities characterized by cellular excess, including accumulation of neural progenitor cells in the periventricular, hippocampal, cerebellar and olfactory bulb regions of the brain. To explore the long-term pathophysiological consequences of BAX/BAK deficiency in a stem cell niche, we generated Bak−/− mice with conditional deletion of Bax in Nestin-positive cells. Aged NestinCreBaxfl/flBak−/− mice manifest progressive brain enlargement with a profound accumulation of NeuN- and Sox2-positive neural progenitor cells within the subventricular zone (SVZ). One-third of the mice develop frank masses comprised of neural progenitors, and in 20% of these cases, more aggressive, hypercellular tumors emerged. Unexpectedly, 60% of NestinCreBaxfl/flBak−/− mice harbored high-grade tumors within the testis, a peripheral site of Nestin expression. This in vivo model of severe apoptotic blockade highlights the constitutive role of BAX/BAK in long-term regulation of Nestin-positive progenitor cell pools, with loss of function predisposing to adult-onset tumorigenesis.

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Acknowledgements

We thank E Smith for editorial and graphics assistance, R Segal, R Folkerth and C Stiles for helpful discussions, and S Rodig and the Harvard Medical School Rodent Histopathology and Brigham and Women's Hospital, Specialized Histopathology cores for technical support. This work was supported by NIH Grants 5R01CA050239 and 1P01CA142536 to LDW, NIH Grant 5K08HL103847 to SGK and the Todd J Schwartz Memorial Fund.

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Authors and Affiliations

  1. Department of Pediatric Oncology and the Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    S G Katz, J K Fisher & L D Walensky

  2. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    S G Katz & K L Ligon

  3. Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    M Correll

  4. Department of Pathology, Harvard Medical School, Boston, MA, USA

    R T Bronson & K L Ligon

  5. Department of Medical Oncology and the Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    K L Ligon

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Correspondence to L D Walensky.

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Katz, S., Fisher, J., Correll, M. et al. Brain and testicular tumors in mice with progenitor cells lacking BAX and BAK. Oncogene 32, 4078–4085 (2013). https://doi.org/10.1038/onc.2012.421

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