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
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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