Scientific American Article - Stem Cells: The Real Culprits in Cancer?

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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 F. e and 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 son 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 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 of s 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 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 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.

________________________________________

MICHAEL F. CLARKE and MICHAEL W. BECKER worked together in e's

laboratory at the University of Michigan at Ann Arbor, where breast

tumor stem cells were first isolated in 2003. e is now associate

director, as well as professor of cancer biology and of medicine, at

the Stanford Institute for Stem Cell Biology and Regenerative

Medicine. He continues to work on identifying cancer stem cells and

the mechanisms by which they, as well as normal stem cells,

regenerate. Becker is assistant professor of medicine in the

hematology and oncology division of the University of Rochester

Medical Center. Becker's research focus is characterizing leukemic

stem cells, and his clinical work centers on peripheral blood and

bone marrow transplantation. MORE TO EXPLORE: The Reversal of Tumor

Growth. Armin C. Braun in Scientific American, Vol. 213, No. 5, pages

75-83; November 1965. The Proteus Effect: Stem Cells and Their

Promise for Medicine. Ann B. Parson. ph Henry Press, 2004.

Context, Tissue Plasticity, and Cancer: Are Tumor Stem Cells Also

Regulated by the Microenvironment? Mina J. Bissell and Mark A.

LaBarge in Cancer Cell, Vol. 7, pages 17-23; January 2005. Leukaemia

Stem Cells and the Evolution of Cancer-Stem-Cell Research. J.

P. Huntly and D. Gilliland in Nature Reviews Cancer, Vol. 5, No.

4, pages 311-321; April 2005. Stem Cells and Cancer: Two Faces of

Eve. F. e and Margaret Fuller in Cell, Vol. 124, pages

1111-1115; March 24, 2006.