Stem cells: A route to cancer's source?

[Angel]

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 anti-cancer 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 Robert Weinberg, a cancer geneticist at the Whitehead Institute in Cambridge, Massachusetts. "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 John 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, Michael Clarke, now of Stanford, succeeded in finding cancer stem cells in breast tumors. Clarke 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. Peter Dirks of the University of Toronto identified similar stemlike cells in human brain tumors, and last year Dr. C. Parker 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. Gary 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 experience 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 Johns 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 anti- cancer 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," Vogelstein said.
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.
Gregory 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 Clarke 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," 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."