Scientists Weigh Stem Cells' Role as Cancer Cause

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December 21, 2007

Scientists Weigh Stem Cells' Role as Cancer Cause

By GINA KOLATA

Within the next few months, researchers at three medical centers expect to start

the first test in patients of one of the most promising - and contentious -

ideas about the cause and treatment of cancer.

The idea is to take aim at what some scientists say are cancerous stem cells -

aberrant cells that maintain and propagate malignant tumors.

Although many scientists have assumed that cancer cells are immortal - that they

divide and grow indefinitely - most can only divide a certain number of times

before dying. The stem-cell hypothesis says that cancers themselves may not die

because they are fed by cancerous stem cells, a small and particularly dangerous

kind of cell that can renew by dividing even as it spews out more cells that

form the bulk of a tumor. Worse, stem cells may be impervious to most standard

cancer therapies.

Not everyone accepts the hypothesis of cancerous stem cells. Skeptics say

proponents are so in love with the idea that they dismiss or ignore evidence

against it. Dr. E. Kern, for instance, a leading pancreatic cancer

researcher at s Hopkins University, said the theory was more akin to

religion than science.

At stake in the debate is the direction of cancer research. If proponents of the

stem-cell theory are correct, it will usher in an era of hope for curing

once-incurable cancers.

If the critics are right, the stem-cell enthusiasts are heading down a blind

alley that will serve as just another cautionary tale in the history of medical

research.

In the meantime, though, proponents are looking for ways to kill the stem cells,

and say that certain new drugs may be the solution.

" Within the next year, we will see medical centers targeting stem cells in

almost every cancer, " said Dr. Max S. Wicha, director of the University of

Michigan Comprehensive Cancer Center, one of the sites for the preliminary

multiple-institution study that begins in the next few months (the other

participating institutions are Baylor College of Medicine in Houston and the

Dana-Farber Cancer Institute in Boston).

" We are so excited about this, " Dr. Wicha said. " It has become a major thrust of

our cancer center. "

At the National Cancer Institute, administrators seem excited, too.

" If this is real, it could have almost immediate impact, " said R. Allan Mufson,

chief of the institute's Cancer Immunology and Hematology Branch.

The cancer institute is financing the research, he said, and has authorized Dr.

Mufson to put out a request for proposals, soliciting investigators to apply for

cancer institute money to study cancer stem cells and ways to bring the research

to cancer patients. The institute has agreed to contribute $5.4 million.

" Given the current fiscal situation, which is terrible, it's a surprising

amount, " Dr. Mufson said. " We actually asked for less, " he added, but the cancer

institute's executive committee asked that the amount be increased.

Proponents of the theory like to use the analogy of a lawn dotted with

dandelions: Mowing the lawn makes it look like the weeds are gone, but the roots

are intact and the dandelions come back.

So it is with cancer, they say. Chemotherapy and radiation often destroy most of

a tumor, but if they do not kill the stem cells, which are the cancer's roots,

it can grow back.

Cancerous stem cells are not the same as embryonic stem cells, the cells present

early in development that can turn into any cell of the body. Cancerous stem

cells are different. They can turn into tumor cells, and they are characterized

by distinctive molecular markers.

The stem-cell hypothesis answered a longstanding question: does each cell in a

tumor have the same ability to keep a cancer going? By one test the answer was

no. When researchers transplanted tumor cells into a mouse that had no immune

system, they found that not all of the cells could form tumors.

To take the work to the next step, researchers needed a good way to isolate the

cancer-forming cells. Until recently, " the whole thing languished, " said Dr.

E. Dick, director of the stem cell biology program at the University of

Toronto, because scientists did not have the molecular tools to investigate.

But when those tools emerged in the early 1990s, Dr. Dick found stem cells in

acute myelogenous leukemia, a blood cancer. He reported that such cells made up

just 1 percent of the leukemia cells and that those were the only ones that

could form tumors in mice.

Yet Dr. Dick's research, Dr. Wicha said, " was pretty much ignored. " Cancer

researchers, he said, were not persuaded - and even if they had accepted the

research - doubted that the results would hold for solid tumors, like those of

the breast, colon, prostate or brain.

That changed in 1994, when Dr. Wicha and a colleague, Dr. e, who is

now at Stanford, reported finding cancerous stem cells in breast cancer

patients.

" The paper hit me like a bombshell, " said Weinberg, a professor of

biology at M.I.T. and a leader in cancer research. " To my mind, that is

conceptually the most important paper in cancer over the past decade. "

Dr. Weinberg and others began pursuing the stem-cell theory, and researchers now

say they have found cancerous stem cells in cancers of the colon, head and neck,

lung, prostate, brain, and pancreas.

Symposiums were held. Leading journals published paper after paper.

But difficult questions persisted. One problem, critics say, is that the math

does not add up. The hypothesis only makes sense if a tiny fraction of cells in

a tumor are stem cells, said Dr. Bert Vogelstein, a colon cancer researcher at

s Hopkins who said he had not made up his mind on the validity of the

hypothesis.

But some studies suggest that stem cells make up 10 percent or even 40 percent

or 50 percent of tumor cells, at least by the molecular-marker criterion. If a

treatment shrinks a tumor by 99 percent, as is often the case, and 10 percent of

the tumor was stem cells, then the stem cells too must have been susceptible,

Dr. Vogelstein says.

Critics also question the research on mice. The same cells that can give rise to

a tumor if transplanted into one part of a mouse may not form a tumor elsewhere.

" A lot of things affect transplants, " Dr. Kern, the s Hopkins researcher,

said, explaining that transplanting tumors into mice did not necessarily reveal

whether there were stem cells.

Other doubts have been raised by Dr. Kornelia Polyak, a researcher at the

Dana-Farber Cancer Institute. Dr. Polyak asked whether breast cancer cells

remain true to type, that is, whether stem cells remain stem cells and whether

others remain non-stem cells? The answer, she has found, is " not necessarily. "

Cancer cells instead appear to be moving targets, changing from stem cells to

non-stem cells and back again. The discovery was unexpected because it had been

thought that cell development went one way - from stem cell to tumor cell - and

there was no going back.

" You want to kill all the cells in a tumor, " Dr. Polyak said. " Everyone assumes

that currently-used drugs are not targeting stem cell populations, but that has

not been proven. "

" To say you just have to kill the cancer stem cell is oversimplified, " she

added. " It's giving false hope. "

The criticisms make sense, Dr. Weinberg said. But he said he remained swayed by

the stem cell hypothesis.

" There are a lot of unanswered questions, mind you, " he said. " Most believe

cancer stem cells exist, but that doesn't mean they exist. We believe it on the

basis of rather fragmentary evidence, which I happen to believe in the aggregate

is rather convincing. "

Dr. Wicha said he was convinced that the theory was correct, and said it

explained better than any other hypothesis what doctors and patients already

know.

" Not only are some of the approaches we are using not getting us anywhere, but

even the way we approve drugs is a bad model, " he said. Anti-cancer drugs, he

noted, are approved if they shrink tumors even if they do not prolong life. It

is the medical equivalent, he said, of mowing a dandelion field.

He said the moment of truth would come soon, with studies like the one planned

for women with breast cancer.

The drug to be tested was developed by Merck to treat Alzheimer's disease. It

did not work on Alzheimer's but it kills breast cancer stem cells in laboratory

studies, Dr. Wicha says.

The study will start with a safety test on 30 women who have advanced breast

cancer. Hopes are that it will be expanded to find out if the drug can prolong

lives.

" Patient survival, " Dr. Wicha said, " is the ultimate endpoint. "

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