[ RadSafe ] Cancer stem cells linked to radiation resistance

Sat Nov 4 17:11:09 CST 2006

Dan,

     The following web address is to the following text which is the Abstract for the complete article.  Unfortunately, if one doesn't have a current subscription to Nature the full text or a .pdf version costs $30.
  I suggest that you inquire with the person listed at the bottom of the Abstract for additional informatioin, i.e. "
  Correspondence to: Jeremy N. Rich1,2,5,6 Correspondence and requests for materials should be addressed to J.N.R. (Email: rich0001 at mc.duke.edu)."

  Best regards,

  Roy Herren

  http://www.nature.com/nature/journal/vaop/ncurrent/abs/nature05236.html

  Letter  Nature advance online publication 18 October 2006 | doi:10.1038/nature05236; Received 1 June 2006; Accepted 7 September 2006; Published online 18 October 2006
  Glioma stem cells promote radioresistance by preferential activation of the DNA damage response  Shideng Bao1,2, Qiulian Wu1,2, Roger E. McLendon2,3, Yueling Hao1,2, Qing Shi1,2, Anita B. Hjelmeland1,2, Mark W. Dewhirst4, Darell D. Bigner2,3 and Jeremy N. Rich1,2,5,6
  Top of page   Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies1, but radiotherapy remains only palliative2 because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of tumour cells expressing CD133 (Prominin-1), a marker for both neural stem cells and brain cancer stem cells3, 4, 5, 6, is enriched after radiation in gliomas. In both cell culture and the brains of immunocompromised mice, CD133-expressing glioma cells survive ionizing radiation in increased proportions relative to most tumour cells, which lack CD133. CD133-expressing tumour cells isolated from both human glioma xenografts and primary patient glioblastoma specimens
 preferentially activate the DNA damage checkpoint in response to radiation, and repair radiation-induced DNA damage more effectively than CD133-negative tumour cells. In addition, the radioresistance of CD133-positive glioma stem cells can be reversed with a specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results suggest that CD133-positive tumour cells represent the cellular population that confers glioma radioresistance and could be the source of tumour recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a therapeutic model for malignant brain cancers.

  Top of page

   Department of Surgery,   
   Preston Robert Tisch Brain Tumor Center,   
   Department of Pathology,   
   Department of Radiation Oncology,   
   Department of Medicine, and,   
   Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA 
  Correspondence to: Jeremy N. Rich1,2,5,6 Correspondence and requests for materials should be addressed to J.N.R. (Email: rich0001 at mc.duke.edu).

Dan W McCarn <hotgreenchile at gmail.com> wrote:
  Dear Group:

Does anyone have any of the publications that I can lay my hands on about
Duke's research? It seems that my officemate at Shell suddenly developed
symptoms and had surgery last week for glioblastoma. He and his family
would like to know a little more about their research.

Regards!

Dan ii

Dan W McCarn, Geologist
Albuquerque & Houston

-----Original Message-----
From: radsafe-bounces at radlab.nl [mailto:radsafe-bounces at radlab.nl] On Behalf
Of ROY HERREN
Sent: Wednesday, October 18, 2006 19:17
To: radsafe at radlab.nl
Subject: [ RadSafe ] Cancer stem cells linked to radiation resistance

http://www.dukemednews.org/news/article.php?id=9922

Public release date: 18-Oct-2006

Contact: Tracey Koepke
koepk002 at mc.duke.edu
919-660-1301
Duke University Medical Center 
Cancer stem cells linked to radiation resistance DURHAM, N.C. -- Certain
types of brain cancer cells, called cancer stem cells, help brain tumors to
buffer themselves against radiation treatment by activating a "repair
switch" that enables them to continue to grow unchecked, researchers at Duke
University Medical Center have found.
The researchers also identified a method that appears to block the cells'
ability to activate the repair switch following radiation treatment. This
finding may lead to the development of therapies for overcoming radiation
resistance in brain cancer as well as other types of cancer, the researchers
said.
Working with animal and cell culture models, the researchers found that a
specific cellular process called the "DNA damage checkpoint response"
appears to enable cancer stem cells to survive exposure to radiation and to
switch on a signal to automatically repair any damage caused to their DNA.
"In recent years, people have hypothesized that cancer stem cells are
responsible for the resistance of malignant tumors to radiation treatment,"
said Jeremy Rich, M.D., senior investigator of the study and an associate
professor of neurology at Duke. "We have shown, for the first time, that
this is indeed the case."
The findings appear Oct. 18, 2006, in the advance online edition of the
journal Nature. The research was supported by the National Institutes of
Health and a number of philanthropic organizations [complete list below].
The type of cancer that the researchers studied, glioblastoma, is highly
resistant to radiation and other forms of treatment and is the most deadly
form of brain cancer worldwide. Although aggressive treatments can destroy
the majority of the cancerous cells, a small fraction of them remain and
often regenerate into even larger masses of tumor cells.
Until recently, scientists knew little about what made these resistant
cells different from those that succumb to radiation treatment. It was
clear, however, that the cells shared characteristics similar to those of
normally functioning nerve stem cells, Rich said.
In the current study, the researchers used glioblastoma tissue removed
from patients during neurosurgery and created two separate models. For one
model, the researchers extracted cells from the tissue and grew them in
cultures in the laboratory. For the second model, they transplanted the
glioblastoma tissue into the frontal lobes of the brains of mice.
The researchers first measured the number of glioma stem cells present in
the original tissue and then administered set doses of ionizing radiation to
the cell cultures and to the mice. In both cases, the researchers observed a
roughly fourfold jump in the number of glioma stem cells present in the
tumor tissue following radiation treatment.
Because ionizing radiation works primarily by causing permanent damage to
the key genetic material of cells, DNA, the researchers hypothesized that
the glioma stem cells survive and multiply by somehow fixing
radiation-induced DNA damage better than the other cancer cells.
To test this, the researchers searched the tissue samples for specific
proteins that are responsible for detecting DNA damage. Using cell samples
taken from both study models, the team examined the DNA damage checkpoint
response both before and after use of ionizing radiation treatments by
testing for activation of the key proteins that detect DNA damage. The
researchers wanted to know whether the cells, following exposure to
radiation treatment, would repair the DNA damage by activating the
checkpoint response or whether they would instead die.
The team found that after ionizing radiation, the DNA damage checkpoint
proteins in glioma stem cells were more highly activated than in other
cancer cells. This heightened activation, the researchers said, leads cancer
stem cells to more effectively repair DNA damage and thus render the cells
less likely to die as a result of the treatment.
In another set of experiments, the researchers treated both the test
animals and the cell cultures with a drug, called debromohymenialdisine,
which is known to inhibit the proteins involved in the activation process.
They added the drug before and after radiation treatment and measured the
number of surviving cancer stem cells.
They found that administering the drug before radiation did little to
change the number of cancer stem cells, but giving the drug in conjunction
with radiation appeared to halt the resistance of cancer stem cells to
radiation. This finding, the researchers said, suggests that use of a
checkpoint inhibitor during radiation ruins the cells' potential to repair
themselves and increases the likelihood that the cells will die.
"Our findings show one pathway in cancer stem cells that promotes the
radiation resistance of glioblastomas," said Rich. "Treatments that target
DNA damage checkpoint response in cancer stem cells may overcome the
radiation resistance and eventually allow us to help even greater numbers of
cancer patients."
###
Other researchers involved in the study were Shideng Bao, Qiulian Wu,
Roger McLendon, Yueling Hao, Qing Shi, Anita Hjelmeland, Mark Dewhirst and
Darell Bigner.
The philanthropic organizations that supported the research include the
Childhood Brain Tumor Foundation, the Pediatric Brain Tumor Foundation of
the United States, the Damon Runyon Cancer Research Foundation, the Sidney
Kimmel Foundation for Cancer Research, Accelerate Brain Cancer Cure, and the
Duke Comprehensive Cancer Center Stem Cell Initiative. 

Roy Herren

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