From: Subject: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response : Abstract : Nature Date: Fri, 22 Dec 2006 17:35:13 +0100 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C725EF.8963D0A0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.3028 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C725EF.8963D0A0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.nature.com/nature/journal/v444/n7120/abs/nature05236.html;jsessionid=7F2C3AA2A83904E2248E2244D40ED3CB Glioma stem cells = promote radioresistance by preferential activation of the DNA damage = response : Abstract : Nature
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Nature 444, 756-760 (7 December 2006) | doi:10.1038/nature05236; = Received 1=20 June 2006; Accepted 7 September 2006; Published online 18 October = 2006

Glioma stem cells promote radioresistance by preferential = activation=20 of the DNA damage response

Shideng Bao1,2,=20 Qiulian Wu1,2,=20 Roger E. McLendon2,3,=20 Yueling Hao1,2,=20 Qing Shi1,2,=20 Anita B. Hjelmeland1,2,=20 Mark W. Dewhirst4,=20 Darell D. Bigner2,3=20 and Jeremy N. Rich1,2,5,6

  1. Department of Surgery,
  2. Preston Robert Tisch Brain Tumor Center,
  3. Department of Pathology,
  4. Department of Radiation Oncology,
  5. Department of Medicine, and,
  6. Department of Neurobiology, Duke University Medical = Center, Durham,=20 North Carolina 27710, USA

Correspondence to: Jeremy N. Rich1,2,5,6=20 Correspondence and requests for materials should be addressed to J.N.R.=20 (Email: rich0001@mc.duke.edu).

=

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Ionizing radiation represents the most effective therapy = for=20 glioblastoma (World Health Organization grade IV glioma), one of the = most lethal=20 human malignancies1,=20 but radiotherapy remains only palliative2=20 because of radioresistance. The mechanisms underlying tumour = radioresistance=20 have remained elusive. Here we show that cancer stem cells contribute to = glioma=20 radioresistance through preferential activation of the DNA damage = checkpoint=20 response and an increase in DNA repair capacity. The fraction of tumour = cells=20 expressing CD133 (Prominin-1), a marker for both neural stem cells and = brain=20 cancer stem cells3,=20 4,=20 5,=20 6,=20 is enriched after radiation in gliomas. In both cell culture and the = brains of=20 immunocompromised mice, CD133-expressing glioma cells survive ionizing = radiation=20 in increased proportions relative to most tumour cells, which lack = CD133.=20 CD133-expressing tumour cells isolated from both human glioma xenografts = and=20 primary patient glioblastoma specimens preferentially activate the DNA = damage=20 checkpoint in response to radiation, and repair radiation-induced DNA = damage=20 more effectively than CD133-negative tumour cells. In addition, the=20 radioresistance of CD133-positive glioma stem cells can be reversed with = a=20 specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results = suggest=20 that CD133-positive tumour cells represent the cellular population that = confers=20 glioma radioresistance and could be the source of tumour recurrence = after=20 radiation. Targeting DNA damage checkpoint response in cancer stem cells = may=20 overcome this radioresistance and provide a therapeutic model for = malignant=20 brain cancers.

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