Stem Cells: The Real Culprits in Cancer?
This article is from the current issue of Scientific American - it
provides a very good understanding of the role of stem cells in cancers.
http://www.sciam.com/article.cfm?chanID=sa006&colID=1&articleID=000B1BED
-0C0A-1498-8C0A83414B7F0000
Stem Cells: The Real Culprits in Cancer? A dark side of stem
cells--their potential to turn malignant--is at the root of a handful
of cancers and may be the cause of many more. Eliminating the disease
could depend on tracking down and destroying these elusive killer cells
By Michael F. Clarke and Michael W. Becker
After more than 30 years of declared war on cancer, a few important
victories can be claimed, such as 85 percent survival rates for some
childhood cancers whose diagnoses once represented a death sentence.
In other malignancies, new drugs are able to at least hold the
disease at bay, making it a condition with which a patient can live.
In 2001, for example, Gleevec was approved for the treatment of
chronic myelogenous leukemia (CML). The drug has been a huge clinical
success, and many patients are now in remission following treatment
with Gleevec. But evidence strongly suggests that these patients are
not truly cured, because a reservoir of malignant cells responsible
for maintaining the disease has not been eradicated.
Stem cells' power to self-renew already exempts them from the rules.
Conventional wisdom has long held that any tumor cell remaining in
the body could potentially reignite the disease. Current treatments
therefore focus on killing the greatest number of cancer cells.
Successes with this approach are still very much hit-or-miss,
however, and for patients with advanced cases of the most common
solid tumor malignancies, the prognosis remains poor. Moreover, in
CML and a few other cancers it is now clear that only a tiny
percentage of tumor cells have the power to produce new cancerous
tissue and that targeting these specific cells for destruction may be
a far more effective way to eliminate the disease. Because they are
the engines driving the growth of new cancer cells and are very
probably the origin of the malignancy itself, these cells are called
cancer stem cells. But they are also quite literally believed to have
once been normal stem cells or their -immature offspring that have
undergone a malignant transformation. This idea--that a small
population of malignant stem cells can cause cancer--is far from new.
Stem cell research is considered to have begun in earnest with
studies during the 1950s and 1960s of solid tumors and blood
malignancies. Many basic principles of healthy tissue genesis and
development were revealed by these observations of what happens when
the normal processes derail. Today the study of stem cells is
shedding light on cancer research. Scientists have filled in
considerable detail over the past 50 years about mechanisms
regulating the behavior of normal stem cells and the cellular progeny
to which they give rise. These fresh insights, in turn, have led to
the discovery of similar hierarchies among cancer cells within a
tumor, providing strong support for the theory that rogue stem like
cells are at the root of many cancers. Successfully targeting these
cancer stem cells for eradication therefore requires a better
understanding of how a good stem cell could go bad in the first place.
Orderly Conduct.
The human body is a highly compartmentalized system made up of
discrete organs and tissues, each performing a function essential to
maintaining life. Individual cells that make up these tissues are
often short-lived, however. The skin covering your body today is not
really the same skin that you had a month ago, because its surface
cells have all since sloughed off and been replaced. The lining of
the gut turns over every couple of weeks, and the life span of the
platelets that help to clot blood is about 10 days. The mechanism
that maintains a constant population of working cells in such tissues
is consistent throughout the body and, indeed, is highly conserved
among all complex species. It centers on small pools of long-lived
stem cells that serve as factories for replenishing supplies of
functional cells. This manufacturing process follows tightly
regulated and organized steps wherein each generation of a stem
cell's offspring becomes increasingly specialized. This system is
perhaps best exemplified by the hematopoietic family of blood and
immune cells. All the functional cells found in the blood and lymph
arise from a single common parent known as the hematopoietic stem
cell (HSC), which resides in bone marrow.
The HSC pool represents less than 0.01 percent of bone marrow cells
in adults, yet each of these rare cells gives rise to a larger,
intermediately differentiated population of progenitor cells. Those
in turn divide and differentiate further through several stages into
mature cells responsible for specific tasks, ranging from defending
against infection to carrying oxygen to tissues. By the time a cell
reaches that final functional stage, it has lost all ability to
proliferate or to alter its destiny and is said to be terminally
differentiated. The stem cells themselves meanwhile remain
undifferentiated, a state they maintain through their unique capacity
for self-renewal: to begin producing new tissues, a stem cell divides
in two, but only one of the resulting daughter cells might proceed
down a path toward increasing specificity. The other daughter may
instead retain the stem cell identity. Numbers in the overall stem
cell pool can thus remain constant, whereas the proliferation of
intermediate progenitors allows populations of specific hematopoietic
cell types to expand rapidly in response to changing needs. The
capacity of stem cells to re-create themselves through self-renewal
is their most important defining property. It gives them alone the
potential for unlimited life span and future proliferation. In
contrast, progenitors have some ability to renew themselves during
proliferation, but they are restricted by an internal counting
mechanism to a finite number of cell divisions. With increasing
differentiation, the ability of the progenitors' offspring to
multiply declines steadily. The practical significance of these
distinctions can be observed when hematopoietic stem cells or their
descendants are transplanted. After the bone marrow of a mouse is
irradiated to destroy the native hematopoietic system, progenitor
cells delivered into the marrow environment can proliferate and
restore hematopoiesis temporarily, but after four to eight weeks
those cells will die out. A single transplanted hematopoietic stem
cell, on the other hand, can restore the entire blood system for the
lifetime of the animal.
The hematopoietic system's organization has been well understood for
more than 30 years, but similar cellular hierarchies have recently
been identified in other human tissues, including brain, breast,
prostate, large and small intestines, and skin. Principles of
regulated stem cell behavior are also shared across these tissues,
including specific mechanisms for controlling stem cell numbers and
for directing decisions about the fates of individual cells. Several
genes and the cascades of events triggered by their activity--known
as genetic pathways--play key roles in dictating stem cells' fate and
function, for example. Among these are signaling pathways headed by
the Bmi-1, Notch, Sonic hedgehog and Wnt genes. Yet most of these
genes were first identified not by scientists studying stem cells but
by cancer researchers, because their pathways are also involved in
the development of malignancies.
Many such similarities between stem cells and cancer cells have been
noted. The classical definition of malignancy itself includes cancer
cells' apparent capacity to survive and multiply indefinitely, their
ability to invade neighboring tissues and to migrate (metastasize) to
distant sites in the body. In effect, the usual constraints that
tightly control cellular proliferation and identity seem to have been
lifted from cancer cells.
Normal stem cells' power to self-renew already exempts them from the
rules limiting life span and proliferation for most cells. Stem
cells' ability to differentiate into a broad range of cell types
allows them to form all the different elements of an organ or tissue
system. A hallmark of tumors, too, is the heterogeneity of cell types
they contain, as though the tumor were a very disorderly version of a
whole organ. Hematopoietic stem cells have been shown to migrate to
distant parts of the body in response to injury signals, as have
cancer cells. In healthy stem cells, strict genetic regulation keeps
their potential for unlimited growth and diversification in check.
Remove those control mechanisms, and the result would be some-thing
that sounds very much like malignancy. These commonalities, along
with growing experimental evidence, suggest that failures in stem
cell regulation are how many cancers get started, how they perpetuate
themselves, and possibly how malignancies can spread.
Achilles' Heel
The presence of stem cells in certain tissues, especially those with
high cell turnover such as the gut and the skin, seems to be an
overly complicated and inefficient system for replacing damaged or
old cells. Would it not appear to make more sense for an organism if
every cell could simply proliferate as needed to supply replacements
for its injured neighbors? On the surface, perhaps--but that would
make every cell in the body a potential cancer cell. Malignancies are
believed to arise when an accumulation of "oncogenic" changes to key
genes within a cell leads to the abnormal growth and transformation
of that cell. Gene mutations typically happen through a direct
insult, such as the cell being exposed to radiation or chemicals, or
simply through random error when the gene is improperly copied before
cell division.
Because the rare stem cells are the only long-lived cells in the
organs where most cancers develop, they represent a much smaller
potential reservoir for cumulative genetic damage that could
eventually lead to cancer. Unfortunately, because stem cells are so
long-lived, they also become the most likely repository for such
damage. Indeed, stem cells' longevity would explain why many cancers
develop decades after tissues are subjected to radiation--the initial
injury may be only the first in a series of mutations required to
transform a healthy cell into a malignant one. In addition to
accumulating and preserving these oncogenic scars, a stem cell's
enormous proliferative capacity makes it an ideal target for
malignancy. Because nature so strictly regulates self-renewal, a cell
population already possessing that ability would need fewer
additional mutations for malignant transformation than would cells
lacking that capacity.
With these considerations in mind, several possible paths to
malignancy become apparent.
In one model, mutations occur in the stem cells themselves, and their
resulting loss of control over self-renewal decisions produces a pool
of stem cells predisposed to malignancy. Subsequent additional
oncogenic events that trigger proliferation of the malignant cells
into a tumor might happen in the stem cells or in their descendants,
the committed progenitor cell population.
A second model holds that oncogenic mutations initially occur in stem
cells but that the final steps in transformation to cancer happen
only in the committed progenitors. This scenario would require the
progenitors' lost self-renewal capacity to be somehow reactivated.
Current evidence supports both models in different cancers. And at
least one example exists of both processes playing a role in
different stages of the same disease. Chronic myelogenous leukemia is
a cancer of the white blood cells caused by the inappropriate fusion
of two genes. Insertion of the resulting fused gene will transform a
normal hematopoietic stem cell into a leukemia stem cell.
Untreated, CML invariably progresses to an acute form known as CML
blast crisis. Catriona Jamieson and Irving Weissman, both then at the
Stanford University School of Medicine, demonstrated that in patients
who progressed to CML blast crisis, the specific additional genetic
events responsible for this more virulent version of the disease had
conferred the ability to self-renew on certain progenitor cells.
Steady Pursuit
Over the past decade, evidence that stem cells could become malignant
and that only certain cancer cells shared a variety of traits with
stem cells strengthened the idea that the driving force underlying
tumor growth might be a subpopulation of stem like cancer cells. The
theory has a longer history, but in the past the technology to prove
it was lacking. By the 1960s a few scientists were already beginning
to note that groups of cells within the same tumor differed in their
ability to produce new tumor tissue. In 1971 C. H. Park and his
colleagues at the University of Toronto showed that within a culture
of cells taken from an original, or "primary," myeloma (a cancer
affecting plasma cells in bone marrow), the cells displayed
significant differences in their ability to proliferate. At the time,
Park's group could not interpret this phenomenon decisively, because
at least two explanations were possible: all the cells might have had
the ability to multiply in culture but by chance only some of them
did, or else a hierarchy of cells was present in the tumor and cancer
stem cells were giving rise to cells that were nontumorigenic, or
incapable of proliferation.
Destroy the engine driving the disease, leaving nontumorigenic cells
to die off.
Philip J. Fialkow of the University of Washington had already
demonstrated in 1967 that the stem cell model was probably the
correct one for leukemia. Using a cell-surface protein marker called
G-6-PD, which can identify a cell's lineage, Fialkow showed that in
some women with leukemia, both the tumorigenic cells as well as their
more differentiated nontumorigenic progeny had all arisen from the
same parent cell. These early studies were critical in the
development of the stem cell model for cancer, but they were still
limited by researchers' inability to isolate and examine different
cell populations within a tumor. A key event in stem cell biology,
therefore, was the commercial availability, beginning in the 1970s,
of an instrument called a flow cytometer, which can automatically
sort different living cell populations based on the unique surface
markers they bear. A second crucial event in the evolution of cancer
stem cell studies was the advent during the 1990s of conclusive tests
for self-renewal.
Assays to establish self-renewal in human cells did not exist until
Weissman of Stanford and John E. Dick of the University of Toronto
developed methods that allowed normal human stem cells to grow in
mice. Using flow cytometry and this new mouse model, Dick began in
1994 to publish a series of seminal reports identifying cancer stem
cells in leukemia. In 2003 Richard Jones of Johns Hopkins University
identified a cancer stem cell population in multiple myeloma. Earlier
the same year our own laboratory group at the University of Michigan
at Ann Arbor had published the first evidence of cancer stem cells in
solid tumors. By transplanting sorted populations of cells from human
breast tumors into mice, we were able to confirm that not all human
breast cancer cells have the same capacity to generate new tumor
tissue. Only one subpopulation of the cells was able to re-create the
original tumor in the new environment. We then compared the
phenotype, or physical traits, of those new tumors with that of the
patient samples and found that the profile of the new tumors
recapitulated the original. This finding indicated that the
transplanted tumorigenic cells could both self-renew and give rise to
all the different cell populations present in the original tumor,
including the nontumorigenic cells. Our study attested to the
presence of a hierarchy of cells within a breast cancer similar to
those identified in blood malignancies.
Since then, the investigation of cancer stem cell biology has
exploded, as labs across the world continue to find similar
subpopulations of tumorigenic cells in other forms of cancer. In
2004, for example, the laboratory of Peter Dirks of the University of
Toronto identified cells from primary human central nervous system
tumors with the capacity to regenerate the entire tumor in mice. In
addition, he found a high number of the purported cancer stem cells
present in one of the fastest-growing forms of human brain cancer,
medulloblastoma, compared with far fewer tumorigenic cells found in
less aggressive brain tumor types.
A related area of recent intensive investigation is also providing
support for the cancer stem cell model. The signaling environment, or
niche, in which tumors reside appears to strongly influence the
initiation and maintenance of malignancy. Studies of normal body
cells as well as of stem cells have already established the essential
role of signals emanating from surrounding tissue and the supportive
extracellular matrix in sustaining a given cell's identity and in
directing its behavior. Normal cells removed from their usual context
in the body and placed in a dish have a tendency to lose some of
their differentiated functional characteristics, for example. Stem
cells, in contrast, must be cultured on a medium that provides
signals telling them to remain undifferentiated, or they will quickly
begin proliferating and differentiating--seemingly as though that is
their default programmed -behavior, and only the niche signals hold
it in check.
In the body, stem cell niches are literal enclaves surrounded by
specific cell types, such as stromal cells that form connective
tissue in the bone marrow. With a few exceptions, stem cells always
remain in their niche and are sometimes physically attached to it by
adhesion molecules. Progenitor cells, on the other hand, move away
from the niche, often under escort by guardian cells, as they become
increasingly differentiated. The importance of niche signaling in
maintaining stem cells' undifferentiated state and in keeping them
quiescent until they are called on to produce new cells suggests that
these local environmental signals could exert similar regulatory
control over cancer stem cells. Intriguing experiments have shown,
for example, that when transplanted into a new niche, stem cells
predisposed to malignancy because of oncogenic mutations will
nonetheless fail to produce a tumor. Conversely, normal stem cells
transplanted into a tissue environment that has been previously
damaged by radiation do give rise to tumors.
Many of the same genetic pathways identified with signaling between
stem cells and their niche have been associated with cancer, which
also suggests a role for the niche in the final transition to
malignancy. For example, if malignant stem cells were being held in
check by the niche but the niche was somehow altered and expanded,
the malignant stem cell pool would have room to grow as well. Another
possibility is that certain oncogenic mutations within cancer stem
cells could permit them to adapt to a different niche, again letting
them increase their numbers and expand their territory. Still a third
alternative is that mutations might allow the cancer stem cells to
become independent of niche signals altogether, lifting environmental
controls on both self-renewal and proliferation.
Closing In
The implications of a stem cell model of cancer for the way we
understand as well as treat malignancies are clear and dramatic.
Current therapies take aim against all tumor cells, but our studies
and others have shown that only a minor fraction of cancer cells have
the ability to reconstitute and perpetuate the malignancy. If
traditional therapies shrink a tumor but miss these cells, the cancer
is likely to return. Treatments that specifically target the cancer
stem cells could destroy the engine driving the disease, leaving any
remaining nontumorigenic cells to eventually die off on their own.
Circumstantial evidence supporting this approach already exists in
medical practice. Following chemotherapy for testicular cancer, for
example, a patient's tumor is examined to assess the effects of
treatment. If the tumor contains only mature cells, the cancer
usually does not recur and no further treatment is necessary. But if
a large number of immature-looking--that is, not fully
differentiated--cells are present in the tumor sample, the cancer is
likely to return, and standard protocol calls for further chemotherapy.
Whether those immature cells are recent offspring that indicate the
presence of cancer stem cells remains to be proved, but their
association with the disease prognosis is compelling. Stem cells
cannot be identified based solely on their appearance, however, so
developing a better understanding of the unique properties of cancer
stem cells will first require improved techniques for isolating and
studying these rare cells. Once we learn their distinguishing
characteristics, we can use that information to target cancer stem
cells with tailored treatments. If scientists were to discover the
mutation or environmental cue responsible for conferring the ability
to self-renew on a particular type of cancer stem cell, for instance,
that would be an obvious target for disabling those tumorigenic
cells. Encouraging examples of this strategy's promise have been
demonstrated by Craig T. Jordan and Monica L. Guzman of the
University of Rochester. In 2002 they identified unique molecular
features of malignant stem cells believed to cause acute myeloid
leukemia (AML) and showed that the cancer stem cells could be
preferentially targeted by specific drugs. Last year they reported
their discovery that a compound derived from the feverfew plant
induces AML stem cells to commit suicide while leaving normal stem
cells unaffected.
Some research groups are hoping to train immune cells to recognize
and go after cancer stem cells. Still others are exploring the use of
existing drugs to alter niche signaling in the hope of depriving
cancer stem cells of the environmental cues that help them thrive.
Yet another idea under investigation is that drugs could be developed
to force cancer stem cells to differentiate, which should take away
their ability to self-renew. Most important is that cancer
investigators are now on the suspects' trail. With a combination of
approaches, aimed at both targeting genetic pathways unique to the
maintenance of cancer stem cells and disrupting the cross talk
between tumor cells and their environment, we hope to be able soon to
find and arrest the real culprits in cancer.