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