Source of cancer stem cells' resistance to radiation discovered
16 February 2009
Cancer stem cells, which generate and maintain tumour growth in many
types of cancers, are relatively resistant to the ionizing radiation
often used as therapy for these conditions.
Part of the reason, say researchers at Stanford University School of
Medicine, is the presence of a protective pathway meant to shield normal
stem cells from DNA damage. When the researchers blocked this pathway,
the cells became more susceptible to radiation.
“Our ultimate goal is to come up with a therapy that knocks out the
cancer stem cells,” said Robert Cho, MD, a clinical instructor of
pediatrics. “If you irradiate a tumour and kill a lot of it but leave
the cancer stem cells behind, the tumour has the ability to grow back.”
As a result, patients can relapse months or years after seemingly
Cho and radiation oncologist and post-doctoral fellow Maximilian
Diehn, MD, PhD, are co-first authors of the research, published in the 4
February issue of the journal Nature. They collaborated with
scientists at Stanford and City of Hope National Medical Center to
conduct the research. They studied breast epithelial stem cells from
humans and mice to unravel why cancer stem cells are more resistant to
radiation than other cancer cells.
“Since cancer stem cells appear to be responsible for driving and
maintaining tumour growth in many tumours, it is critical to understand
the mechanisms by which these cells resist commonly used therapies such
as chemotherapy and radiotherapy,” said Diehn. “Ultimately, we hope to
improve patient outcomes by developing therapeutic approaches that
directly target cancer stem cells or that overcome their resistance
The origin of cancer stem cells is still under debate. Some may arise
from normal adult stem cells gone awry. Others may represent specialized
cells from adult tissues that have acquired a stem-cell-like state
through a series of mutations. What’s clear is that cancer stem cells
can reconstitute an entire tumour cell population when transplanted into
an immune-deficient animal, and destroying them is likely to be critical
in order to stop the growth and spread of the disease.
But unlike most cells in the body, which are relatively expendable,
stem cells are not that easy to kill. Among the millions of easily
replaceable minions that carry out the everyday drudgery of living, the
much more rare and versatile stem cells comprise a veritable ruling
class. It makes sense to protect such a valuable asset.
Diehn and Cho found that, in this case, the protection takes the form
of the increased expression of proteins that can bind and deactivate
reactive oxygen species, or ROS. These highly unstable small molecules
bounce around wreaking havoc on a cell’s DNA and proteins. Although they
occur naturally in dividing cells, they are also important mediators of
the therapeutic radiation and some chemotherapies doctors use to fight
The researchers knew that blood stem cells had previously been found
to have lower levels of reactive oxygen species than non-stem cells.
They wondered whether the same would be true for breast epithelial stem
cells. They found that normal breast stem cells from mice have lower ROS
levels than do non-stem cells, and that this characteristic was shared
by cancer stem cells from both humans and mice.
They found out why when they looked at gene expression levels: the
human breast cancer stem cells were churning out much higher levels of
antioxidant proteins than were non-stem cells. Antioxidants capture and
disarm ROS before they can cause much damage. This may explain why
cultured mouse breast cancer stem cells were less likely than other
cancer cells to experience DNA damage after ionizing radiation.
“The resistance observed in the breast cancer stem cells seems to be
a similar if not identical mechanism to that used by normal stem cells,”
said Michael Clarke, MD, the associate director of the Stanford
Institute for Stem Cell and Regenerative Medicine and the Karel H. and
Avice N. Beekhuis Professor in Cancer Biology. Clarke, who discovered
the first cancer stem cells in a solid tumour, is a member of the
Stanford Cancer Center and the senior author of the research.
“Although your body would normally eliminate cells with chromosomal
damage, it also needs to spare those cells responsible for regenerating
and maintaining the surrounding tissue — the stem cells,” Clarke
explained. “It’s protective.”
This protection backfires in the case of cancer, however. The
researchers found that, in mice with mammary tumours, cancer stem cells
with low ROS levels were about twice as likely as other tumour cells to
survive a course of ionizing radiation. Similar results were seen in
human head and neck cancers that had been transplanted into mice.
The discovery could lead to a new approach to treating cancer.
Blocking the activity of an important antioxidant called glutathione
made the cancer stem cells significantly more sensitive to killing by
radiation. Figuring out how to do something similar in human tumours
could have important therapeutic benefits.
“Basically we need to figure out a way to inactivate that protective
mechanism in cancer cells while sparing normal cells,” said Clarke. For
many patients, it’s a life-or-death question.
“It’s like battling weeds,” said Cho, of the cancer stem cells’
ability to come back even stronger than before. “You can go through a
big field with a weed whacker, but the weeds are going to come back
unless you get the roots.”
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