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Myeloma Matters at the Malaghan - Cancer Stem Cells under attack
by Mike Berridge January 2006
Malaghan Institute of Medical Research, PO Box 7060, Wellington
The Malaghan Institute is taking on the cancer stem cell.
In a quirk of fate that began some 30 years ago with attempts
to fingerprint a rare population of blood-forming stem cells
in the bone marrow, researchers at the Malaghan Institute
have this year developed a novel assay for cancer stem cells.
What is remarkable and unique about this assay is that the
cell target is a quiescent or slowly-dividing cancer cell
with properties similar to those of stem cells. In contrast,
most current anticancer drugs target rapidly-dividing tumour
cells but not the cancer stem cell.
The cancer stem cell assay will be used to screen potential
anticancer drugs that block a vital life support system used
by these stem cells. Surprisingly, the target is in the outer
lipid membrane of the cell in contrast to the vast majority
of current anticancer drugs that act inside the cell to block
cogs in the machinery of the cell division cycle. As a result,
side effects that are the hallmark of many current cancer
drugs should be greatly reduced. In joint research with synthetic
organic chemist, Professor Robin Smith at Otago University,
and with funding from the Genesis Oncology Trust, designer
drugs will be built that position in the outer membrane of
the cell, blocking a stress release pathway used by cancer
stem cells as well as other cancer cells.
Almost fifty years after their discovery, cancer stem cells
remain an elusive target in our anticancer drug armoury. This
is because they exist as rare subpopulations of tumour cells
that divide infrequently in a protected environment and therefore
resist cytotoxic drugs that kill dividing cells. Cancer stem
cells, in common with other stem cell populations in the body,
are characterised by an ability to self-renew slowly without
loss of proliferative potential. Alternatively, they can produce
“committed” daughter cells that are unable to self-renew.
These daughter cells divide rapidly but have a limited proliferative
potential. With normal stem cells, these “committed”
cells eventually generate the large numbers of functional cells
that make up, for example, the blood and immune systems, and
the linings of the body. With cancer, proliferating cells that
cannot self-renew, predominate and maturation to generate non-dividing
functional cells is often blocked or slowed down. In support
of the stem cell model of cancer, cancer stem cells have recently
been demonstrated to comprise only a few percent of tumour cells
while the vast majority of dividing cells in the tumour are
non-tumorigenic, that is, they are unable to self-renew and
reproduce tumours when transplanted into suitable recipients.
Cancer stem cells have now been demonstrated in a wide range
of different cancers including breast, colon, neuroblastoma
and haematological malignancies.
In May of last year, Professor Michael Clarke from the University
of Michigan Medical School was an invited keynote speaker at
the NZ Society for Oncology conference in Wellington where he
talked about his pioneering research on breast cancer stem cells,
including their isolation, assay and gene expression profiling.
The irony is that cancer can now be considered to be a disease
of non-dividing cancer stem cells, rather than of rapidly-proliferating
cells which form the bulk of the tumour but cannot sustain tumour
growth indefinitely. If cancer cure is our ultimate goal, then
we must find ways to seek out and eradicate the cancer stem
cell.
The November 2005 issue of Myeloma Matters featured an article
on Stem Cells by Scott LaFee, San Diego Union-Tribune writer.
In that article, the potential of normal stem cell populations
to repair and regenerate damaged tissues and organs was contrasted
with their dark side when genetic change turns them into rogue
cancer stem cells. The rogue cancer stem cells will then produce
dividing tumour cells that form most of the tumour mass.
The focus of attention of most cancer research and pharmaceutical
cancer drug development has been rapidly-dividing tumour cells,
rather than quiescent cancer stem cells. As a consequence, while
cancer growth may be contained and tumours may shrink, remissions
are often transient, drug resistance a major problem, and drug
withdrawal results in aggressive return of the cancer. This
was shown in recent mathematical modelling of chronic myeloid
leukaemia (CML) where treatment with the new wonder-drug, gleevec/imanitib,
resulted in complete and sustained clinical remission, but drug
withdrawal, even 3-4 years later, resulted in explosive return
of Bcr/Abl-positive leukaemic cells, consistent with residual
cancer stem cells surviving drug treatment. Multiple myeloma
shares many of the treatment characteristics of CML and is therefore
likely to be a stem cell disease.
Cancer is a large family of several hundred genetic diseases.
Fuelled by cancer genome projects, knowledge about genetic changes
involved in cancer has exploded in recent years, to the point
where the number of molecular targets defined by genetic change
approximates the number of different types of cancer involved
and includes oncogenes, tumour suppressor genes, DNA repair
genes and epigenetic changes. Despite this new knowledge, progress
in developing new drugs based on this information has been exceedingly
slow over the past 10-15 years and there is no sign that the
floodgates are about to open. Why are we making so little progress
utilizing the plethora of genetic information on cancer now
available? The answer probably lies in the fact that many of
the genetic changes identified in cancer reflect the properties
of proliferating tumour cells rather than characteristics of
quiescent cancer stem cells, which, although they harbour cancer
genes, may not express these altered genes. Loss of ability
to self-renew would then release the information contained in
these silent yet aberrant genes, resulting in uncontrolled cell
proliferation.
What is desperately needed is more knowledge about the basic
cell biology of the tumour-perpetuating cancer stem cell. New
knowledge about this cancer stem cell will lead to the development
of novel targeting strategies that are specific for this elusive
cell. For half a century now, cancer has largely outsmarted
us by masquerading as a disease of proliferating cells, whereas
in fact the essence of the disease is a minor subpopulation
of non-dividing stem cells. If our hypothesis is correct, then
strategies the target non-dividing tumour cells that self-renew
in a protected hypoxic environment and thus employ glycolytic
metabolism for energy production purposes, may provide the ultimate
answer to the dichotomy that exists between increased knowledge
about cancer yet slower progress in identifying new and relevant
cancer drug targets.
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