Interesting article on stem cells

[Guest guest]

Stem cells promise medical miracles, but there's a dark side, too

By LaFee

UNION-TRIBUNE STAFF WRITER

August 17, 2005

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Photo Researchers

It's probably not surprising that cancer stem cells (top) bear a remarkable

resemblance to stem cells (above). A new wave of research puts stem cells

gone bad at the root of many cancers.

Human stem cells boast a kind of immortality. They are able to precisely

copy themselves, over and over, for our entire lives.

We shed and regrow our outer layer of skin cells once every 27 days or so -

roughly 1,000 new skins in the average lifetime. But the stem cells from

which those outer skin cells originate are essentially the same ones we were

born with - and the same ones with which we will die.

It's this enduring quality, combined with their remarkable ability to

develop into almost any kind of cell needed, that has elevated stem cells to

iconic medical marvel, the means one day of perhaps repairing - even

regenerating - tissues and organs damaged and destroyed by disease, accident

and age.

But there's a dark side to this power of self-renewal. It's called cancer.

And evidence grows daily that many - if not all - types of cancers are the

consequence of normal stem cells gone bad.

" To use a Star Wars analogy, it's Jedi Knights and Darth Vader, " said Dr.

Evan Snyder, director of the Stem Cells and Regeneration Program at the

Burnham Institute in La Jolla. " Normal stem cells have these amazing powers

to differentiate into other cells, to move about the body, to go where

they're needed. Cancer stem cells have the same skills, but they use them

for evil. "

Think of cancer as a disease of uncontrolled self-renewal, said Tannishtha

Reya, an assistant professor of pharmacology and cancer biology at Duke

University. Normal stem cells renew themselves under precise and carefully

regulated conditions so their progeny are exactly what is intended and

needed. Cancer stem cells do not. They simply grow amok, producing countless

lesser copies that corrupt and may eventually kill. A tumor is, in this

sense, really just an aberrant organ.

For decades, researchers have focused on treating cancer through reduction.

If a therapy killed cancerous cells, if it reduced the size of a tumor, it

was deemed a success. Clinical trials to test new cancer drugs were - and

are - largely based on how well they reduce the number of detectable cancer

cells or shrink tumors.

The tragedy, of course, is that such victories are often transient. The

cancer returns, sometimes worse than before. " There are many things that

shrink tumors, " said Dr. Max Wicha, director of the University of Michigan's

Comprehensive Cancer Center, " but hardly any that affect the life spans of

patients. "

Again, the villain may well be cancer stem cells, the small subset of cells

that have the capacity to perpetuate cancer and which are resistant, if not

impervious, to most common cancer drugs and treatments. Chemotherapy and

radiation may kill 99 percent of the cells in a malignant tumor, but if the

remaining 1 percent contain cancer stem cells, the tumor will likely grow

back.

" We're talking about a fundamental paradigm change, " said Wicha, whose

particular interest is how breast cancer cells grow and metastasize.

" We need to develop drugs targeted at the tumor's stem cells. If we are to

have any real cures in advanced breast cancer, it will be absolutely

necessary to eliminate these cells. What this means for women with cancer is

that, for the first time, we can define what we believe are the important

cells, the cells that determine whether the cancer will come back or be

cured. Before this, we didn't even know there were such cells. "

Recent breakthroughs

Wicha isn't exaggerating. Though the idea of cancer deriving from some sort

of " germ cell " was first proposed more than 100 years ago by ish

embryologist Beard, it was largely overlooked until 40 years ago when

researchers noticed that only one in 100 human leukemia cells could

propagate in a Petri dish.

Still, the notion languished until Dick of the University of Toronto

harvested a tiny minority of cancer stem cells in acute myelogenous

leukemia, the most common form of the disease. These cells, he reported in

1995, were the only ones that indefinitely generated new cancer cells,

fueling the disease's growth.

Dick's work got some people thinking - and looking. In 2003, Dr.

e, a professor of internal medicine at the University of Michigan, and

colleagues discovered stem cells in breast cancer. A few months later, other

researchers reported finding them in forms of human brain cancer.

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JOHN GIBBINS / Union-Tribune

" Cancer stem cells have the same skills (as normal stem cells,) but they use

them for evil. " - Evan Snyder, La Jolla's Burnham Institute.

" Now people are looking for stem cells in all the major cancer types, " said

Wicha. " There are new reports that they've found them in prostate and lung

cancers. I think it's just a matter of time before we find stem cells

associated with all kinds of cancer. "

Cancer stem cells keep tumors growing, but where do these stem cells come

from? In some cases, researchers now say, they may derive from normal stem

cells. In fact, said Reya at Duke, among all of the different types of cells

in a tissue, stem cells may be the most sensitive to becoming cancerous.

The vast majority of mature cells in the human body have limited life spans.

" To become cancerous, these cells would somehow have to accumulate a set of

necessary mutations in a certain order in a relatively short time. They

would need first mutations that prevent death, then mutations enabling

self-renewal, " said Reya. " This would seem to be a very hard thing to do.

" On the other hand, stem cells already have long life spans in which they

multiply many times and may thus accrue mutations more readily.

Additionally, stem cells actively self-renew. All a stem cell would have to

do to become a cancer is acquire the mutation that takes the brakes off

self-renewal. This suggests that stem cells may often be the target of

mutations and thus the cell of origin for many cancers. "

As odd as it sounds, the majority of cancer cells are not especially

dangerous. They cannot self-renew. They have finite life spans and tend to

die before causing much harm.

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The work of e at the University of Michigan and others dramatically

illustrates the point. e and his colleagues found that only a small

percentage of cells in breast cancer were stem cells, just 1 percent to 10

percent. Mice injected with just a handful of these cancer stem cells

developed tumors. Mice injected with run-of-the-mill breast cancer cells did

not.

" You could inject 20,000 of the cancer cells that don't self-renew and the

mice wouldn't get cancer, " said Wicha. " But a relative few stem cells can

cause the disease. "

It's become hot science to find new corollaries and connections between

normal stem cells and cancer stem cells. For example, a study by Dr. Gennadi

Glinsky and colleagues at the Sidney Kimmel Cancer Center in La Jolla found

that an 11-gene sequence associated with the proliferation of normal stem

cells appears also to be active in the development of cancerous tumors.

The researchers, writing in the June issue of the Journal of Clinical

Investigation, evaluated 1,122 cancer patients diagnosed with 10 types of

cancer. In patients whose tumors had spread quickly, the scientists found

the 11-gene sequence to be consistently active and the cancer more likely to

be fatal, regardless of type.

A similar finding was reported out of work at the National Institute of

Neurological Disorders and Stroke in Bethesda, Md. There, researchers

identified a particular protein - nucleostemin - that appears to control

proliferation in both healthy and cancerous stem cells by behaving like a

molecular switch, turning cell division on and off.

Fighting back

As evidence mounts that mutant stem cells are the strength and Achilles'

heel of cancer, new challenges come into sharper focus.

One hurdle is actually finding and identifying cancer stem cells. They are

exceedingly rare. In mice, for example, multipotent progenitor cells

comprise just 0.05 percent of bone-marrow cells.

(Stem cells are categorized by their ability to differentiate. Totipotent

cells can become anything. They are able to create whole organisms.

Pluripotent cells cannot create whole organisms but can differentiate into

most kinds of cells. Multipotent stem cells can become only a limited

variety of cells, such as bone or blood.)

Second, they're hard to recognize. Generally speaking, cancer stem cells

look like normal stem cells, and in some tissues, scientists don't even have

a definitive test to distinguish stem cells from other cells.

Picking out the particular subset of cancer stem cells is laborious and

complicated. Researchers extract subsets of cells from suspect tissue and

transplant them to determine which subsets have the ability to propagate and

regrow the tumor. Those that do are, presumably, cancer stem cells.

Simpler methods, of course, are being sought: streamlined tests that would

identify subtle but distinct differences between cells, a chemical signature

or surface protein marker, for example. Researchers are confident they'll

find such distinguishing characteristics, but it will take time.

Even when they've learned how to identify and target cancer stem cells,

scientists will need to figure out how to effectively kill them without

killing healthy cells as well.

" It will be important in any new treatment to spare stem cells like those

found in the gut, brain and bone marrow because without them, you die, " said

Wicha.

But stem cells, unlike cells farther down the line of differentiation, are

notably tough. They have to be to live as long as you do. Stem cells have

learned to circumvent apoptosis, or cell death. Factors or conditions that

would kill other cells or induce them to commit suicide do not apply to stem

cells. They appear to be resistant to most current forms of chemotherapy.

In a letter published in the June 30 issue of the journal Nature, a team of

American, Japanese and Australian scientists reported that Gleevec, the

first approved drug to target cancer at the molecular level, reduced

leukemic cell production but did not appear to deplete the population of

leukemic stem cells.

" In all probability, cancer stem cells simply have more protective factors

than other cells, " said Snyder at the Burnham Institute.

New or modified drugs may eventually provide part of the answer.

Complementary drugs and therapies might be used to attack different aspects

of the disease simultaneously, such as radiation combined with therapeutics

that disrupt angiogenesis, the process used by tumors to attract new blood

vessels needed for survival.

Snyder has proposed using stem cells themselves as a vehicle of attack.

In 2000, while working at Children's Hospital in Boston, Snyder reported in

preliminary studies that neural stem cells in mice were able to " sense "

brain injuries, migrate to the damaged areas and repopulate the regions with

healthy tissue.

" What if we could use normal stem cells modified to carry anti-cancer

drugs? " he asked. " These modified cells might actually chase down cancer

stem cells and kill them. "

In last year's annual meeting of the Society of Neuroscience in San Diego,

Snyder described experiments in which mice with brain tumors received an

injection of human embryonic stem cells modified to carry a gene that

expresses an anticancer molecule TRAIL.

Snyder said the modified cells homed in on the cancer, apparently by

following chemical signals emitted by immune system molecules, and pumped

out enough TRAIL to reduce tumor size by up to 70 percent.

Such a therapy might be particularly useful against intracranial

glioblastoma, an aggressive type of brain tumor that killed one of Snyder's

closest friends. Intracranial glioblastoma is invariably fatal. It cannot be

cured using conventional techniques because the cancer creates numerous

satellite tumors. The five-year survival rate for patients is 5 percent.

Human clinical trials for Snyder's stem cell approach might begin within two

years. He is hopeful such trials will provide proof of concept, if not a

precise treatment.

" The goal is to kill cancer stem cells, which appear to be the root of the

disease, " he said.

If that is possible, then there may eventually be no such thing as an

incurable cancer. Tumors and such would be treatable and beatable. They

could be made to go away and never come back.

" And that, " said Reya at Duke University, " would be a great thing. "

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