The Bad Seed
Rare stem cells appear to drive cancers
While some brain tumors are treatable, many
are a speedy death sentence despite the best efforts of
physicians. A neurosurgeon may carefully cut out every
sign of a brain tumor, but new cancer cells quickly arise
to take the original tumor's place. The cancer may even
overcome toxic chemicals and intense beams of radiation,
powerful weapons that kill rapidly dividing cells and
suppress the growth of many tumors.
TARGET. Traditional cancer therapies (top) kill rapidly
dividing tumor cells (red) but may spare stem cells (blue)
that can give rise to a new tumor. In theory, killing
cancer stem cells (bottom) should halt a tumor's growth
and perhaps even lead to its disappearance.
Why are many brain tumors and other cancers
so difficult to treat? The answer may lie in the cancer
stem cell, an old idea that has been given new life in
For decades, cancer researchers have wrestled
with two competing visions of tumors. In one scenario,
all the cells of a tumor are pretty much the same. That
is, they have an equal capacity to divide and form new
In the other scenario, only a few select
cells from a tumor have the capacity to initiate new,
full-fledged tumors. These bad seeds are the cancer stem
Oddly enough, it took the study of leukemia,
a blood cancer in which there typically is no actual tumor,
to initially prove the existence of cancer stem cells.
A decade ago, John E. Dick of the University of Toronto
led a research team that harvested cancer cells from people
with leukemia and showed that only some of these blood
cells could reproduce the disease in rodents.
Until recently, scientists weren't sure
whether stem cells also play a role in malignancies producing
solid tumors. Early last year, however, Michael F. Clarke
of the University of Michigan Medical School in Ann Arbor
and his colleagues reported that a small minority of human
breast cancer cells, perhaps just 1 in 100, forms tumors
when implanted into mice. Later in 2003, two research
teams independently presented evidence that cancer stem
cells underlie brain tumors as well.
"I think the cancer–stem-cell
hypothesis will apply to every kind of cancer," says
Dick. Researchers are now racing to identify tumor-forming
stem cells in skin, lung, pancreatic, ovarian, prostate,
and many other cancers. "We simply need to know what
the cells are that give rise to the tumor. It's an unknown
for virtually all tumor types," says Tyler Jacks,
director of the Center for Cancer Research at the Massachusetts
Institute of Technology (MIT).
Biologists are also exploring how cancer
stem cells originate. Researchers suspect that the dangerous
cells may arise from mutations in the normal stem cells
that sustain various tissues. This type of inquiry is
so hot that Stanford University has just created an institute
that brings together cancer researchers and stem cell
biologists in an unprecedented research marriage.
The concept of cancer stem cells could change
notions of how cancers spread and how tumors should be
treated. For example, some current cancer drugs may turn
out to kill most cells in a tumor but to spare the stem
cells, thereby setting the stage for a relapse. "If
we don't eliminate those cells, then they will just re-form
tumors," says Clarke.
One in a million
Normal stem cells in healthy organs have
two defining characteristics. First, they show a kind
of immortality that scientists call self-renewal because
these cells can divide indefinitely to produce more copies
of themselves. Second, a stem cell is unspecialized, but
it can produce progeny that mature into the various cell
types of, say, the brain or the immune system. Once this
maturation occurs, the stem cell heirs may divide rapidly
but only a limited number of times.
The blood system has the best-described
normal stem cells. In the 1980s, Dick and other researchers
characterized the mouse stem cell that resides in bone
marrow. This hematopoietic stem cell can give rise to
both red blood cells and the various white blood cells
of the immune system. In fact, a single mouse hematopoietic
stem cell can reconstitute an animal's entire blood supply.
After finding the mouse stem cell, Dick
and his colleagues began looking for a human counterpart
that could form human blood cells when transplanted into
immune-deficient mice. As they struggled with that challenge,
they wondered whether human leukemia cells would reproduce
in immune-deficient mice. The researchers reported in
1997 that some of the human cancer cells that they harvested
from patients would grow in the lab animals.
"We showed that roughly one cell in
a million, when transplanted into a mouse, had the capacity
to regrow the disease," says Dick.
Those rare cells, the researchers concluded,
could be considered cancer stem cells. The team then characterized
those dangerous cells by distinctive proteins on their
surfaces. It turned out that the leukemia stem cells sport
a protein, called CD34, that healthy hematopoietic stem
cells also carry but other cells don't. Furthermore, the
human-leukemia stem cells consistently lack another protein,
CD38, that most other leukemia cells have.
Since then, scientists have unearthed stem
cells in other blood cancers, most recently multiple myeloma.
In this disease, antibody-making plasma cells accumulate
in and destroy bone marrow.
However, the plasma cells don't divide very
often, notes William Matsui of Johns Hopkins Medical Institutions
in Baltimore. So, he and other investigators have long
suspected that some other cell generates the multitude
of cancerous plasma cells.
In the March 15 Blood, Matsui and his colleagues
present evidence that the stem cells in multiple myeloma
are a subset of immune cells known as B cells. The stem
cells both self-renew and develop into the mature plasma
cells that mark multiple myeloma, the researchers found.
That finding makes sense because earlier
work showed that B cells give rise to plasma cells during
normal blood development, says Matsui.
The concept of cancer stem cells has been
around since at least the 1950s. "The hypothesis
was right, but [scientists] couldn't come up with the
experiments needed to prove it," says Clarke.
Aware of Dick's work on leukemia stem cells,
Clarke in the 1990s became attracted to the idea that
solid tumors also have stem cells. One day, when examining
cells from a testicular cancer, he noticed that a few
of the cells bore a surface protein common to immature
fetal cells. "That made me think, 'Holy cow, this
is a stem cell disease,'" recalls Clarke.
The biologist decided to look for stem cells
in a more common disease, breast cancer. In a strategy
developed by Clarke's colleague Muhammad Al-Hajj, the
researchers initially sorted human breast cancer cells
into populations defined by their surface molecules. The
scientists then transplanted the various cell populations
into the mammary tissue of immune-deficient mice to see
whether they would grow tumors.
The team eventually homed in on a group
of cells bearing a protein called CD44 but lacking other
surface proteins common to breast cells. Whereas it takes
injections of many thousands of unsorted breast cancer
cells to trigger a tumor in such rodents, transplanting
as few as 100 of the CD44-bearing cancer cells reliably
generated the cancer. The scientists could even isolate
the same subset of cells from the new tumor and transplant
them into another mouse to invariably generate another
This study "caused people to wake up,"
says Dick. The scientific community found the work, appearing
in the April 1, 2003 Proceedings of the National Academy
of Sciences, to be compelling evidence that a rare subset
of cancer cells creates tumors in the breast, he notes.
It also prompted investigators to consider whether other
solid tumors harbor stem cells.
Not long after Clarke's paper came out,
two research groups working independently reported that
cells with stem cell characteristics were present in children's
brain tumors. One team was headed by Peter B. Dirks of
the Hospital for Sick Children in Toronto; the other,
by Harley I. Kornblum of the University of California,
Dick's work with leukemia stem cells had
inspired Dirks to think differently about solid brain
tumors. "A lot of cancer research involves studying
the whole tumor mass," explains Dirks. "People
tend to grind up the solid mass and not consider each
individual cell in the tumor."
Taking a different approach, he and his
colleagues separated brain tumor samples into individual
cells. Next, the team looked among those cells for a surface
molecule that had been recently identified on stem cells
in a healthy human brain.
Dirks' team hypothesized that this molecule,
CD133, might also mark brain tumor stem cells. Indeed,
small numbers of cells displaying CD133 reside in a variety
of brain tumors, the researchers found.
In a laboratory dish, the cells reproduced
and also differentiated into the same varieties of brain
cells seen in the original tumors, the researchers reported
in the Sept. 15, 2003 Cancer Research. In contrast, the
growth of other tumor cells isolated petered out.
In the Dec. 9, 2003 Proceedings of the National
Academy of Sciences, Kornblum and his colleagues published
their own report that CD133-bearing cells isolated from
pediatric brain tumors behave as stem cells. The two studies'
results are "remarkably similar," Kornblum says.
His group also described transplanting the
newly identified cells into the brains of newborn rats.
The cells migrated throughout the brain, produced nerve
cells and other kinds of brain cells, and continued to
proliferate for up to a month.
Kornblum's group is now conducting longer
studies to see whether brain tumors will arise in the
animals receiving the transplants. Dirks and his colleagues
have also begun transplanting cells into the brains of
rodents for a similar test.
A dangerous cell
One of the main issues regarding cancer
stem cells is whether they're normal stem cells gone awry
or differentiated cells that have acquired stem cell characteristics.
The former scenario appeals to most scientists, although
they acknowledge it's largely unproved.
Because it can replicate endlessly, a normal
stem cell is a "very dangerous cell" that's
poised on the edge of becoming cancerous, says Dick. The
potentially endless reproduction of a stem cell also allows
enough time for cancer-promoting mutations to accumulate
in such a cell, he explains.
The cancer–stem-cell hypothesis could
explain why many cancers are resistant to radiation and
drugs. Normal stem cells are unusually hardy and possess
molecular pumps similar to the ones that some cancer cells
use to flush out chemotherapy agents, notes Kornblum.
The discovery of cancer stem cells is forcing
scientists to reconsider how they look for tumor-fighting
drugs. "Everyone has been concentrating on proliferation,"
says Clark. Traditionally, researchers screen for compounds
that kill dividing tumor cells, but stem cells are often
quiescent, only occasionally spawning progeny that then
"The biology of the tumor you see may
not be the same as the biology of the stem cell. You're
never going to cure someone unless you hit the stem cell,"
Scientists battling leukemia, the disease
in which a cancer stem cell was first isolated, have been
focusing on this new target for a few years, says Dick.
As one example, he points to a 2002 study in which Craig
T. Jordan of the University of Kentucky Medical Center
in Lexington and his colleagues identified compounds that
specifically kill leukemia stem cells derived from patients.
The research on cancer stem cells also threatens
to upend thinking on how cancers spread, or metastasize.
Conventional theories hold that metastasis is an evolutionary
process in which a small number of cells within a primary
tumor gradually accumulate the genetic mutations that
enable them to spread to other tissues and establish new
tumors. An alternative model now being put forth is that
many cells in a primary tumor spread in the body, but
a second tumor arises only when a rare stem cell reaches
a new site.
Scientists have proposed that identifying
cancer stem cells from various types of tumors will help
them isolate the long-sought normal stem cells in tissues
such as the prostate gland and the breast. "Tracing
back from the tumor to that cell population will allow
us to identify these critical cells in normal tissue,"
says Jacks, who is a Howard Hughes Medical Institute investigator
"It's a new field and there's a ton
of work that needs to be done," concludes Clarke