Stem cells and cancer/NYT article

[Guest guest]

February 21, 2006

Stem Cells May Be Key to Cancer

By NICHOLAS WADE

One day, perhaps in the distant future, stem cells may help repair

diseased tissues. But there is a far more pressing reason to study

them: stem cells are the source of at least some, and perhaps all,

cancers.

At the heart of every tumor, some researchers believe, lie a handful

of aberrant stem cells that maintain the malignant tissue.

The idea, if right, could explain why tumors often regenerate even

after being almost destroyed by anticancer drugs. It also points to a

different strategy for developing anticancer drugs, suggesting they

should be selected for lethality to cancer stem cells and not, as at

present, for their ability to kill just any cells and shrink tumors.

" I think this is one of the most interesting developments in cancer

research in the last five years, " says Weinberg, a cancer

geneticist at the Whitehead Institute in Cambridge, Mass. " I think

more and more people are accepting it and evidence is accumulating

that cancer stem cells exist in a variety of tumors. "

The idea that cancer cells possess the same properties as stem cells

has been around for many years. Only recently have biologists

developed techniques for identifying stem cells and their presence in

tumors.

Cancer stem cells were first identified in certain types of leukemia

in 1997 by Dick and colleagues at the University of Toronto. They

were harder to spot in solid tumors because biologists did not possess

the means of recognizing the markers — characteristic proteins on the

surface of a cell — that had been developed for a stem cell that makes

red and white blood cells.

But in 2003 Dr. e, now of Stanford, succeeded in finding

cancer stem cells in breast tumors. Dr. e showed that a vast

majority of cells in a human breast tumor were incapable of further

growth. Only a handful were able to seed new cancers, and these

resembled stem cells in their ability to proliferate and generate

mature cells.

In 2004, Dr. Dirks of the University of Toronto identified

similar stemlike cells in human brain tumors, and last year Dr. C.

Gibbs of the University of Florida reported seeing stemlike

cells in bone cancer.

" It's a very challenging population of cells to identify, but thus far

in every cancer in which cells have been carefully screened they have

been found, " said Dr. Gilliland of Harvard.

Biologists are not yet sure how cancer stem cells are generated. It

may be that the stem cells themselves suffer a mutation, or a change

in their DNA instructions, that deranges the strict controls on their

self-renewal. Or possibly their immediate progeny, known as progenitor

cells, suffer some genetic damage after which, instead of developing

into mature cells, they regain the power of self-renewal.

Self-renewal, the key property of stem cells, refers to their ability

to divide unevenly. Other cells divide into two daughter cells, just

as the parent cell does, but a stem cell can divide into a new stem

cell and a progenitor cell. The progenitor cell loses the power of

self-renewal but gains the ability to change or differentiate into the

mature cell types of the tissue served by the stem cell.

After such a division, the number of stem cells in the tissue remains

unchanged because one stem cell has been lost and one created. The

stem cell population thus renews itself as it generates new cells for

the tissue.

The stem cells responsible for maintaining a tissue or an organ can

presumably regulate their own numbers, perhaps by sensing through an

exchange of chemicals when they have a quorum. Cancer stem cells

differ in that they have lost control over their own population size.

The hypothesis explains several otherwise puzzling facts about cancer.

Many of the body's tissues that are most prone to cancer, like the

blood, skin and lining of the gut, are composed of short-lived cells

that suffer high wear and tear.

Yet cells are believed to become malignant only after a series of

mutations has disabled their genetic control systems. How can a skin

cell, which lives only a few weeks, survive long enough to accumulate

the right sequence of mutations?

It is more plausible to suppose that mutations build up in the

self-renewing population of stem cells that maintains the skin and

that lasts throughout a person's lifetime.

Pathologists have long recognized that tumors contain a variety of

cells, including some that are characteristic of the tissue in which

the cancer originates. But not all these cells are equally cancerous.

If the cells from a tumor are injected back into a patient at a

different site, as was done in a 1961 experiment that would now be

considered unethical, more than a million cells must be used before a

new tumor will form.

This supports the idea that only a tiny minority of the cells in a

cancer have the ability to maintain it.

An amazingly successful anticancer drug is Gleevec, used to treat

chronic myelogenous leukemia and three rarer cancers. Many patients

who take Gleevec enjoy complete remission. But the drug does not cure

the disease, which sometimes returns. It seems Gleevec is attacking

not the cancer stem cells but the progenitor cells from which the

cancerous white blood cells are generated.

Though many biologists believe that the cancer stem cell idea is

interesting, not all think that it will lead to new therapies. In the

view of Dr. Bert Vogelstein, a leading cancer researcher at s

Hopkins, everything depends on how much of a tumor consists of cancer

stem cells.

If the proportion is large, as several experiments suggest, then

current anticancer drugs must already be killing them, since they can

kill up to 99 percent of the cells in a tumor. In which case, the idea

is not so helpful.

" So the real attractiveness of the cancer stem cell hypothesis, in my

view, is that if the 1 percent of cells that are left after successful

chemotherapy are really cancer stem cells, then obviously that

provides the rationale for different forms of therapy that target

them, " Dr. Vogelstein said.

Dr. Gilliland, an advocate of the idea, acknowledged that 20 percent

of cells in the solid tumors analyzed so far had stemlike properties.

But with better markers, he said, it may turn out that a much smaller

proportion are true cancer stem cells.

" If the growth of solid cancers were driven by cancer stem cells, it

would have profound implications for cancer therapy, " Dr. Irving

Weissman of Stanford has written. " Therapies that are more

specifically directed against cancer stem cells might result in much

more durable responses and even cures of metastatic tumors, " he and

colleagues said.

If the notion of cancer stem cells is correct, how can they be

eliminated without also killing the normal stem cells that are vital

for maintaining the body's tissues? Researchers hope that the cancer

stem cells, because of their excessive activity, may be more dependent

than normal cells on certain cellular processes and thus will be more

vulnerable to drugs that block those processes.

Dr. Plowman, research director at Genentech, which has

developed several leading anticancer drugs, said that the concept was

significant and that Genentech had made a venture fund investment in

OncoMed, a company founded by Dr. e to develop monoclonal

antibodies against cancer stem cells.

But companies may hold back from broader investment in the field until

the basic biology of cancer stem cells is better understood.

Pharmaceutical companies are " waiting for more academic research

before they take a clear view on how to proceed, " Dr. Weinberg said.

" Our knowledge base is still rather fragmentary, and we need another

year or two of research before we can say to pharmaceutical companies

you should do this or that. "