Scientists Weigh Stem Cells? Role as Cancer Cause

http://www.nytimes.com/2007/12/21/science/21stem.html?ref=health

Dr. Max S. Wicha, a leading researcher of cancerous stem cells.
Scientists Weigh Stem Cells? Role as Cancer Cause

By GINA KOLATA
Published: December 21, 2007

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. Scott E. Kern, for instance, a leading pancreatic
cancer researcher at Johns Hopkins University, said the hypothesis was
more akin to religion than to science.

At stake in the debate is the direction of cancer research. If proponents
of the stem-cell hypothesis 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
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 Dr. 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 hypothesis 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. John E. ***, 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. *** 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. ***?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. Michael Clarke,
who is now at Stanford, reported finding cancerous stem cells in breast
cancer patients.

?The paper hit me like a bombshell,? said Robert 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 hypothesis, 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 Johns Hopkins who said he had not made up his mind on
the validity of the hypothesis.

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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 Johns 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 hypothesis 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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