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Journal of the National Cancer Institute Advance Access originally published online on September 11, 2007
JNCI Journal of the National Cancer Institute 2007 99(18):1410-1414; doi:10.1093/jnci/djm102
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© The Author 2007. Published by Oxford University Press.

BRIEF COMMUNICATION

Examination of the Therapeutic Potential of Delta-24-RGD in Brain Tumor Stem Cells: Role of Autophagic Cell Death

Hong Jiang, Candelaria Gomez-Manzano, Hiroshi Aoki, Marta M. Alonso, Seiji Kondo, Frank McCormick, Jing Xu, Yasuko Kondo, B. Nebiyou Bekele, Howard Colman, Frederick F. Lang, Juan Fueyo

Affiliations of authors: Brain Tumor Center (HJ, CGM, HA, MMA, SK, JX, YK, HC, FFL, JF) and Department of Biostatistics (BNB), The University of Texas M. D. Anderson Cancer Center, Houston, TX; Cancer Research Institute and Comprehensive Cancer Center, University of California, San Francisco, CA (FM); Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan (HA)

Correspondence to: Hong Jiang, PhD, Department of Neuro-Oncology, Unit 1002, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail: hjiang{at}mdanderson.org).

The eradication of brain tumor stem cells is essential for long-term brain tumor remission after treatment. In this study, we examined the therapeutic potential of an oncolytic adenovirus, Delta-24-RGD, targeted to the abnormal p16INK4/Rb pathway in brain tumor stem cells. Four brain tumor stem cell lines from surgical glioblastoma specimens expressed high levels of adenoviral receptors and allowed for efficient viral infection, replication, and oncolysis in an Rb-dependent manner. Delta-24-RGD induced autophagic cell death, as indicated by accumulation of Atg5 and LC3-II protein and autophagic vacuoles. Treatment of xenografts derived from brain tumor stem cells with Delta-24-RGD statistically significantly improved the survival of glioma-bearing mice (means: 38.5 versus 66.3 days, difference = 27.8 days, 95% confidence interval = 19.5 to 35.9 days, P <.001). Analyses of treated tumors showed that Atg5 expression colocalized with viral fiber protein and delineated a wave front of autophagic cells that circumscribed areas of virally induced necrosis. Our results show for the first time that brain tumor stem cells are susceptible to adenovirus-mediated cell death via autophagy in vitro and in vivo.


CONTEXT AND CAVEATS

Prior knowledge

To achieve long-term remission after treatment for brain cancer, it is necessary to eradicate brain tumor stem cells that are resistant to radiation and chemotherapy.

Study design

The therapeutic potential of oncolytic adenovirus Delta-24-RGD targeted to brain tumor cells was tested in vitro using cell lines with stem cell properties that were derived from gliobastoma multiforme tumors and in vivo using a mouse xenograft tumor model.

Contribution

The four cell lines were efficiently infected with an oncolytic adenovirus Delta-24-RGD, which induced autophagic cell death. Mice carrying xenograft tumors that were derived from one of the cell lines survived longer after treatment with Delta-24-RGD than with an inactivated form of the virus.

Implications

Adenovirus-mediated autophagic cell death can be induced in brain tumor cells with properties of stem cells.

Limitations

It is unclear how similar the cell lines developed in this study are to the brain tumor stem cells that exist in human brain cancer or whether the oncolytic adenovirus developed in this study would be efficacious and safe in humans.

 
Manuscript received March 21, 2007; revised June 27, 2007; accepted July 2, 2007.


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