Stem cells seen driving tumors

Boston GlobeDecember 2004

Stem cells have become famous for their ability to heal, spurring hopes that they might one day cure Parkinson’s disease, spinal cord injuries, and a wide variety of ailments. But now a growing number of researchers are concluding that stem cells are also the hidden force behind one of nature’s most feared killers: cancer.

Within each tumor, they believe, lurks a small population of elusive, highly potent cells that drive the tumor’s growth. Under a microscope they appear identical to other cancer cells, but these cancer stem cells hold the power to produce cancerous tumors in much the same way that normal stem cells can regenerate the body’s healthy tissues. They also seem to resist traditional cancer drugs, explaining why patients can be seemingly cured of some cancers only to see the disease return.

In the past two years, cancer stem cells have gone from a theory on the fringes of biology to an idea that is attracting money and talent in cancer research. Last year a scientist at the University of Michigan announced the discovery of stem cells in breast tumors. In the past few months, a form of leukemia and two types of brain cancer were both linked to cancer stem cells, and scientists familiar with unpublished studies said more cancers are likely to follow. The first test in patients of a therapy targeting these stem cells is now getting underway.

The discovery of cancer stem cells provides a promising new target for the war on cancer, and it could also force a profound change in cancer research, say the theory’s growing number of advocates.

Most treatments today are judged by their ability to shrink tumors, but the new results suggest the size of the tumor is all but irrelevant: If doctors can kill the stem cells, the tumor is doomed, but if the stem cells survive it will be back.

“It is mind-blowing,” said Robert A. Weinberg, an MIT scientist who is one of the world’s leading cancer biologists. “The entire mindset of people must now be refocused onto these stem cells.”

Scientists caution that the path ahead will be challenging. Simply finding cancer stem cells is difficult, requiring laborious trial-and-error experiments in which biologists analyze similar-looking cancer cells for the chemical signatures of a stem cell. They then attempt to sift out those cells and see if they cause new cancers to grow. But there are lingering obstacles: Even for many healthy tissues, for instance, there is not yet a definitive test to distinguish stem cells.

The research community is amassing its forces to attack the problem. Harvard University, Harvard Medical School, and the Harvard-affiliated hospitals are organizing a cancer stem-cell program as a part of the recently formed Harvard Stem Cell Institute. This year, the National Cancer Institute has identified cancer stem cells as one of the most important new ideas in cancer research; next year it plans to announce a stem-cell initiative, according to R. Allan Mufson, who is chief of the Cancer Immunology/Hematology Branch at the institute.

In part, the excitement surrounding the idea has come from the growing realization that there are deep connections between the biology of cancer — perhaps the top target of biomedical research over the last three decades — and the rapidly expanding science of stem cells. Researchers say progress in understanding the origins of cancer may also give them tools to unleash the potential of stem cells for healing.

The idea also exerts a powerful emotional pull on doctors who specialize in cancer treatment because it relates directly to one of the cruelest aspects of the disease. Patients can endure surgery, radiation, and near-lethal drugs to fight their tumors, only to watch helplessly as the cancer comes raging back.

“We have agents that will treat almost every cancer,” said Dr. Gary Gilliland, who directs the leukemia program at the Dana-Farber Cancer Institute and is leading Harvard’s new cancer stem cell effort. “But with a few notable exceptions, we don’t cure these cancers.”


Which cells really ause cancer?


Scientists have suspected a link between stem cells and cancer cells for decades. Stem cells, which appear in many tissues in the adult body — from the skin to the blood to the brain — are unique because they have the ability to create large numbers of other cells. Scientists also sometimes refer to stem cells as “immortal” for their unique ability to renew their own ranks, seemingly indefinitely. Cancer cells seem to share some of these qualities, only they are riddled with genetic defects that make them grow into dangerous, uncontrolled masses.

A stem cell “has all the things that we ascribe to a very aggressive cancer,” said John E. Dick, a professor at the University of Toronto.

In 1994, Dick became the first scientist to prove the existence of a cancer stem cell, which combines the profound genetic damage of a cancer cell with the self-renewing capacity of a normal stem cell. In studying a common form of blood cancer called acute myelogenous leukemia, he found that only a small proportion of the leukemia cells were capable of actually causing the cancer. And these cells, he showed, had the same chemical markers as the stem cells found in healthy blood.

But that idea remained an isolated finding until last year, when Dr. Michael Clarke, a professor at the University of Michigan, announced he had found a stem cell in human breast tumors — suddenly suggesting that stem cells could be driving solid tumors as well. In August, a paper in the New England Journal of Medicine linked another form of leukemia to cancer stem cells, and last month, a paper in the prestigious journal Nature showed that two common forms of brain tumors are driven by stem cells.

The brain research, led by Dr. Peter B. Dirks of the University of Toronto and the Hospital for Sick Children in Toronto, looked at cells taken from human brain tumors and identified possible cancer stem cells among them. Dirks showed that as few as 100 of these cells could create an aggressive brain cancer in a mouse. But without these stem cells, even a massive dose of up to 100,000 cancer cells didn’t spark a cancer, according to the paper.

Clarke said last week that in unpublished work he has identified stem cells for another cancer, and believes he has found stem cells for two more types of cancer.

With other cancer scientists now starting to direct their research toward stem cells and new findings bolstering the idea, Clarke said he now receives almost daily invitations to give presentations around the country.

“When I first published this, nobody believed me,” Clarke said. “At this point, I think I am going to die if I take one more plane trip.”

Although the field has only begun to yield useful findings, scientists are already looking for ways to use this knowledge to treat cancer. They believe the key is to home in on the ways in which stem cells differ from normal cells. Radiation and traditional chemotherapy drugs tend to target cells that are dividing quickly and creating large numbers of new cells. Because this rapid division is the trademark of an active cancer, these treatments are generally effective at shrinking the size of tumors — the traditional measure of effectiveness.

Stem cells, by contrast, are usually slow to divide. When a stem cell does divide, it can create long-lived copies of itself — thus ensuring its “immortality.” But a stem cell can also create cells known as progenitor cells that have the power to create a group of new cells that quickly expand in number. Cancer therapies that kill only these quickly dividing cells may appear successful in the short term, but leave the more important stem cells unharmed.

The search for drugs that would specifically target cancer stem cells is underway. Craig T. Jordan, a scientist at the University of Rochester School of Medicine and Dentistry, has been working for years with the cancer stem cells identified in 1994, looking for ways to kill them without hurting normal cells. Two years ago, while still a researcher at the University of Kentucky, he identified a pair of drugs that targeted leukemia stem cells. Recruiting began last month for a trial in Kentucky for people who have relapsed, which is very common, and for other patients who can’t handle the toxicity of the traditional treatment.

Jordan said that in unpublished work he has identified another promising drug treatment, based on a natural plant compound called parthenolide, though he cautioned that any clinical trial of this drug would be at least a year away.

Clarke, Dirks, and other scientists involved in the research said that they are especially interested in developing treatments that can disrupt the ability of the cancer stem cells to replicate themselves. If scientists can find a drug that interferes with this power, then without the “immortal” stem cells, the tumor would simply die.

Dr. Harley I. Kornblum, a leading figure in brain cancer stem cells research, is working on a project to screen large numbers of potential drugs to stop cancer stem cells from replicating indefinitely. Kornblum is director of the neural stem cell research center at the University of California, Los Angeles, and a researcher at the Jonsson Comprehensive Cancer Center there.

Drugs that target cancer stem cells, scientists said, could be used in combination with traditional chemotherapies to heighten their effect. They might also be used in combination with drugs designed to disrupt the ability of tumors to attract the new blood vessels they need to survive, a process called angiogenesis.

Researchers are also actively looking for drugs that might disrupt the ability of cancer cells to leave the primary tumor and start growing elsewhere in the body, a process called metastasis.

Although many aspects of cancer stem cells are still poorly understood — and only a few types have been identified — it may not be necessary to understand them well to tame them, said Dr. Todd R. Golub, director of the cancer program at the Broad Institute and an oncologist at Dana-Farber Cancer Institute.

For example, he said, if a therapy can efficiently destroy all of the direct offspring of the stem cells, then the cancer can be held in check, making it a manageable chronic disease rather than an unpredictable killer.

Newer approaches to cancer drug development may yield drugs that kill cancer stem cells even if scientists have not been able to identify the stem cells.

These drugs, such as Gleevec, are designed to attack very specific aspects of a cancer cell, though some patients treated with Gleevec have begun to suffer relapses.

Cancer has proven an ingenious and frustrating opponent, but even with all the difficult work that now lies ahead, one longtime researcher said that the discovery of cancer stem cells has been like pulling back a great veil.

“Finally,” said Weinberg, “we have come to see the true face of the enemy.”