Within the next few months, researchers at three medical centres expect to start the first test in patients of one of the most promising 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 tumours.

Although many scientists have assumed that cancer cells are immortal, 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 tumour. Worse, stem cells may be impervious to most standard cancer therapies.

Not everyone accepts the hypothesis of cancerous stem cells. Sceptics say proponents are so in love with the idea that they dismiss or ignore evidence against it.

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 centres targeting stem cells in almost every cancer," said Dr Max S Wicha, director of the University of Michigan Comprehensive Cancer Centre, one of the sites for the preliminary study that begins in the next few months.

Proponents of the hypothesis like to use the analogy of a lawn: 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 tumour, but if they do not kill the stem cells, which are the cancer's roots, it can grow back.

The stem-cell hypothesis answered a longstanding question: Does each cell in a tumour have the same ability to keep a cancer going? By one test the answer was no. When researchers transplanted tumour cells into a mouse that had no immune system, they found that not all of the cells could form tumours.

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 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, Dick found stem cells in blood cancer. He reported that such cells made up just 1 per cent of the leukemia cells and that those were the only ones that could form tumours in mice.

Yet Dick's research, Wicha said, "was pretty much ignored."
That changed in 1994, when Wicha and a colleague, Dr Michael Clarke, reported finding cancerous stem cells in breast cancer patients.

Robert Weinberg, a professor of biology at MIT, 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 tumour are stem cells, said Dr Bert Vogelstein, a colon cancer researcher at Johns Hopkins.

Critics also question the research on mice. Other doubts have been raised by Dr Kornelia Polyak, a researcher at the Dana-Farber Cancer Institute. Polyak asked whether breast cancer cells remain true to type. The answer, she has found, is "not necessarily."

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 tumours 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, Wicha says.
"Patient survival," Wicha said, "is the ultimate endpoint."

New York Times