June 26, 2006
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 stemlike 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.
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
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
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
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
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.
Several possible paths to malignancy become apparent.
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.
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 stemlike 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
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
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
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
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
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.
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
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.
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