A new look into cancer's roots

The Baltimore Sun

Scientists hope that someday stem cells will cure diseases.

Pamela Joseph fears that cancer stem cells will kill her first.

As her doctors explain it, stem cells are the source of multiple myeloma, a blood cancer the 56-year-old Clarksville woman has been fighting since 2005. Stem cells might also be the reason that the cancer - which has killed one member of Joseph's family - is incurable.

The notion of stem cells as potential villains is counterintuitive, given their highly publicized promise for repairing damaged tissues and organs. But some experts say that certain stem cells may be just as good at restoring cancers that doctors are trying to eradicate.

Learning how to destroy cancer stem cells, they theorize, might lead to that most elusive of breakthroughs - the cure for cancer.

This is an old notion, only recently revived. Scientists first explored the cancer-stem cell connection nearly 40 years ago but abandoned it when the scientific techniques of the period weren't up to the task.

Now, however, advances in molecular biology and the current boom in stem cell research have spurred renewed interest in the idea - and renewed skepticism.

Scientists at the University of Maryland and the Johns Hopkins University are investigating cancer stem cells, making Baltimore one of the few hubs for the nascent science. In January, the Maryland Stem Cell Commission received four proposals requesting state funding for the research.

"This is a very hot topic," said Dr. Richard J. Jones, one of Joseph's doctors at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

To explain it, Jones compares cancer to a dandelion, that bane of the well-manicured lawn: the flawed adult cells that make up the bulk of a cancer tumor are like dandelion flowers. Like a lawn doctor mowing down the flowers, a cancer doctor uses chemotherapy and radiation to eradicate mature cancer cells.

But just as dandelion flowers return, so, too, does cancer because the offending root - cancerous stem cells - remains intact.

"We have some pretty good lawnmowers," Jones said of cancer treatments. "But they don't get at the stem cells."

The theory holds that cancerous adult cells come from a relatively small number of stem cells. The stem cells can renew themselves through cell division and generate a variety of cell types - properties that make them promising for treating disease.

The same attributes, however, may enable them to become tiny factories that feed and renew cancers.

Simple as the concept seems - stem cells produce mature cancer cells - studying it is a complex matter.

Researchers at the University of Toronto demonstrated in 1971 that only a small percentage of the cancerous cells taken from leukemia-afflicted mice could grow and divide. They called these "tumor stem cells."

Six years later, a group at the University of Arizona developed a way to culture human versions of the cells in the laboratory.

But technological limits prevented those scientists from completely separating stem cells from other cell types, much less proving that stem cells gave rise to mature cancer cells.

"There was a big debate about whether they were actually stem cells," said Anne V. Hamburger, a member of the Arizona team that developed the technique.

Just as importantly, the research failed to produce new therapies, said Hamburger, now a professor of pathology at the University of Maryland Greenebaum Cancer Center.

"The whole idea went out of fashion," she said. "There was no funding for that type of work, so I moved in other directions."

As other scientists followed suit, the research ground to a halt. "It disappeared," Hamburger said. "It was a little mystifying."

A couple of decades later, science caught up to the theory. Researchers developed methods for using antibodies - important proteins of the immune system - to identify and isolate different kinds of cells in the laboratory.

In 1997, John Dick of the University of Toronto made the first definitive identification of cancer stem cells in leukemia. In 2003, Dr. Michael Clarke, now of Stanford, first isolated them from the solid tumors of breast cancer patients and showed that only cells with properties of stem cells generated new cancers.

Since then, cancer stem cells have also been found in brain and lung cancers.

But whether the cells are the source of tumors remains to be proven, according to Kenneth S. Zaret, a cell biologist at Fox Chase Cancer Center in Philadelphia. "That's really the big question now," he said, adding that stem cells might produce some cancers but not others.

The source of cancer stem cells is also unclear, he said. They could start as stem cells or be mature cells that regain stem cell properties because of genetic mutations.

Dr. Martin D. Abeloff, director of Johns Hopkins' cancer center, said the reasons that cancers recur may be complicated.

"For years we've treated people, and their diseases melted away quickly - but then returned," he said. "The concept of having a stem cell would explain part of that. But like most things we deal with, it won't be as straightforward as we would like. It merits, like most research, a healthy skepticism."

Proponents of the cancer stem cell theory also acknowledged many unknowns. "The majority of scientists are still waiting to be convinced," Jones said.

But if the theory pans out, he said, it could transform cancer therapy. Treatments targeting stem cells could lead to longer-lasting remissions or eradication of cancers.

Dr. William Matsui, another Johns Hopkins cancer researcher, said therapies developed for one type of cancer might be applicable to others, because the stem cells at the root of different cancers are likely to be similar. "It holds the potential to be the cure for cancer everyone talks about," he said.

To bolster their argument, the Hopkins scientists hope to produce some hard clinical evidence. They are conducting a clinical trial of Rituxan, a drug that might target the stem cells involved in multiple myeloma - Pamela Joseph's form of cancer.

Multiple myeloma is a blood plasma cell cancer that causes a weakening of the bones, kidney failure, anemia and death. A drug called Gleevec sends the cancer into remission, but it always comes back.

"That drug mows dandelions, but it doesn't get at the root," said Dr. Carol Ann Huff, one of the Hopkins researchers.

Rituxan was largely abandoned as a treatment for multiple myeloma after a 2003 study suggested it was ineffective.

But Huff and her colleagues think it might just take a little patience for the drug to work. Rituxan might take longer than other drugs, they say, but if it destroys the stem cells that lurk in the body and bring the cancer back, the drug might rid patients of the cancer once and for all.

To test the theory, they have added Rituxan to the chemotherapy cocktail some of the patients in the clinical trial receive. If those patients fare better than others, it could be evidence that the drug does target cancer stem cells.

Pamela Joseph decided to join the clinical trial after researching various multiple myeloma therapies with the help of her husband, Malcolm Joseph.

His father, Malcolm Joseph Sr., also developed multiple myeloma and lost the use of one of his arms as a result. Despite that, the retired Army command sergeant continued to drive from his home in New York's Bronx borough to Baltimore to visit family.

"He was a good guy and a tough guy," his son recalls. He succumbed to the disease after three years, in 2004. He was 78 years old.

Doctors diagnosed the same form of cancer in Pamela Joseph less than a year after her father-in-law died. "It was devastating," her husband said. "It's hard to talk about."

During a recent chemotherapy session, Pamela said she's hopeful her doctors' theories about stem cells will help her avoid her father-in-law's fate.

"Who knows? Maybe I'll be the lucky first person," she said, knitting in an armchair at the cancer center as a machine pumped Rituxan into her veins. Her cancer is in remission.

Other previously abandoned drugs might also prove to be effective at eradicating cancer stem cells. "We think the concept is right," Jones said. "But we're not sure we have the right drug."

Meanwhile, scientists at the University of Maryland are testing older drugs and trying to develop new ones for suppressing cancer stem cells. They're also trying to learn whether stem cells collected from cancer patients are sensitive to various chemical compounds.

But it's not easy. Cancer stem cells are difficult to find and attack, said Angelika M. Burger, a drug researcher at Maryland.

"Stem cells never die. They can reproduce; they can sleep and hide away," she said "When they are hidden, they may not be reached by our current drugs."

Burger and colleagues at Maryland requested research funding from Maryland's stem cell commission this year, as did the Hopkins team. The commission is expected to make its awards this month.

Hamburger, now a member of the Maryland research team, has revived her lab work from the 1970s.

"Science has evolved a lot, but the research is still pretty technically difficult to do," she said. And for the time being, she's enjoying the scientific deja vu.

"It's really interesting to see the whole thing cycle around," she said. "There's still a lot of room for proof. But I think there is a lot more acceptance this time."

chris.emery@baltsun.com

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