Stem cells give clues to understanding cancer and make breakthrough
in childhood leukaemia
February 13, 2008 11:06 PM Stem Cell Research
Scientists in Switzerland are uncovering new clues about how cancer
cells grow – and how they can be killed – by studying stem
cells, `blank' cells that have the potential to develop into fully
mature or `differentiated' cells and other scientists in UK have made
a breakthrough in understanding the cause of the most common form of
childhood cancer, acute lymphoblastic leukaemia (ALL). The research
should lead to less aggressive treatment for the disease and could
result in the development of new and more effective drugs, an
international conference on stem cell biology was told last month.
The conference, organised by the European Science Foundation's
EuroSTELLS programme and held in Barcelona on January 10-13, heard
that stem cells and cancer cells share many similar features. For
example the cellular machinery that sends signals between stem cells
to tell them when and how to develop is in many cases similar to the
signalling mechanisms that operate between cancer cells.
On one hand, Professor Ariel Ruiz i Altaba of the University of
Geneva in Switzerland is studying key proteins in stem cells and
cancer stem cells – cancer cells that are later responsible for
tumour growth, the recurrence of tumours and the spread of the cancer
to other parts of the body[1]. Four such proteins, called Sonic
Hedgehog (Shh) and Gli-1, Gli-2 and Gli-3 act through a biochemical
pathway to send important signals between cells. "We have shown that
interfering with Shh signalling decreases the size of tumours, which
is proof of principle that the tumours require the pathway,"
Professor Ruiz i Altaba told the conference participants.
Professor Ruiz i Altaba's team has been experimenting with samples of
brain and other tumours from patients, treating tumour cells and
their cancer stem cells – the cells that continuously replenish the
growing cancer – in the laboratory with chemicals that inhibit the
activity of the Shh pathway and lead to the inhibition of Gli-1. "We
take tumour samples and grow them in a variety of ways," said
Professor Ruiz i Altaba. "When we treat them with inhibitors that
block the Shh-Gli pathway, they all respond, demonstrating that every
tumour we have tested requires this signalling pathway."
Professor Ruiz i Altaba added, "Hedgehog signalling appears to be
involved in many kinds of stem cells and many kinds of cancers.
Specifically, Gli-1 seems to be important for the proliferation of
tumour cells and especially for the proliferation and perpetuation of
cancer stem cells. We think the Gli code, the sum of all Gli
activities, is locked in a `hyperactivating' state in cancer, and if
we can revert it to a repressive state, this could provide a possible
therapeutic approach."
Meanwhile Dr Manel Esteller of the Spanish National Cancer Research
Centre (CNIO) in Madrid has been investigating the way that genes in
cancer cells and stem cells are modified by a process called
methylation[
In a cell not all of the genes are active. Some are rendered `silent'
by the attachment of chemical entities called methyl groups. This is
one of the mechanisms by which a cell can switch genes on and off. It
has become clear that the pattern of DNA methylation is one key
difference between a cell that has become specialised – that is
differentiated – and one that remains undifferentiated.
"We have studied plant DNA and have seen that in undifferentiated
tissue one particular region of the DNA is always unmethylated,
Esteller told the meeting. "In differentiated tissue this same region
is methylated. If we take the undifferentiated cell and add the
methylated gene we get differentiation.
A similar system appears to operate in human cells. And in some
cancer cells there are particular patterns of DNA methylation. "We
have seen that in some leukaemias there is a gene involved in
differentiation that is methylated," Dr Esteller said. "In cultured
cells we see that if we put the unmethylated gene back into the cell,
we stop the growth of the cells in culture, and also in mouse models.
This gene is acting as a tumour suppressor."
The hope is that further investigation of factors such as DNA
methylation could lead to potential new treatments for cancer.
On the other hand, Professor Tariq Enver of the Weatherall Institute
for Molecular Medicine at the University of Oxford presented findings
of his research on acute lymphoblastic leukaemia (ALL), which has now
been published in the journal Science[3].
Professor Enver, who is a EuroSTELLS collaborator and his co-workers,
demonstrated for the first time the existence of cancer stem cells in
ALL. The researchers compared the blood of three-year-old identical
twins, one of whom has the disease while the other is healthy.
The researchers found that both twins had genetically abnormal blood
cells – `pre-leukaemic' stem cells that reside in the bone marrow. It
appears that these cells can either lay dormant or can somehow be
triggered to develop into full-blown leukaemia stem cells.
The researchers showed that these cells arise from an abnormal fusion
of two genes during the mother's pregnancy. Professor Enver
said, "This research means that we can now test whether the treatment
of acute lymphoblastic leukaemia in children can be correlated with
either the disappearance or persistence of the leukaemia stem cell.
Our next goal is to target both the pre-leukaemic stem cell and the
cancer stem cell itself with new or existing drugs to cure leukaemia
while avoiding the debilitating and often harmful side effects of
current treatments."
EuroSTELLS is a EUROCORES programme, managed by the European Medical
Research Councils (EMRC) at the European Science Foundation. Source :
European Science Foundation
http://www.biologyn
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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