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Emphasis on cancer stem cells grows with recruitment of second top scientist

Philip Beachy

Michael Clarke

Irving Weissman

BY AMY ADAMS

As Philip Beachy, PhD, moves his lab from Johns Hopkins University to the Stanford School of Medicine, he brings an additional piece to a puzzle that lies at the heart of the school's cancer research efforts: What is the role of cancer stem cells in the disease's progression?

Beachy, whose work has advanced the study of the molecular pathways used by cancer stem cells and cells in the developing embryo, became professor of developmental biology on Sept. 1. He follows last year's arrival from the University of Michigan of Michael Clarke, MD, who first identified solid tumor stem cells in breast cancer in 2003.

With the addition of Beachy and Clarke, Stanford has taken another step toward cementing its position as a leader in a field that is quickly gaining widespread acceptance. Recent reviews in both the New England Journal of Medicine and Nature tout cancer stem cell research as a likely source of future cancer treatments. True, some researchers question the cells' significance. But a consensus seems to be building that knowledge about these cells will play a pivotal role in developing better ways to combat the disease.

Cancer stem cells are believed to be the cells that continuously replenish cancer, like the spring at the source of a creek. Only the cancer stem cell can form a new cancer. The regular cancer cells, which arise each time the cancer stem cell divides, cause damage by their sheer bulk, yet they alone can't form a new cancer.

Because of the cells' apparent role in cancer, Irving Weissman, MD, who leads both the Stanford Institute for Stem Cell Biology and Regenerative Medicine and the Stanford Comprehensive Cancer Center, has made cancer and leukemia stem cells a primary focus of the school's expanding effort to treat cancer and develop new therapies. He and others believe the reason many cancers return after treatment is that radiation and most forms of chemotherapy kill the quickly dividing cells but leave a significant fraction of the cancer stem cells unharmed. Completely eliminating a cancer means eradicating its stem cells.

"The overall plan is to amalgamate the cancer stem cell work with the cancer gene discovery efforts and translate that into clinical trials at Stanford," Weissman said.

Already collaborations to find new cancer stem cells in solid tumors, basic research into how the cells replenish themselves and work to translate that basic science into the clinic are establishing the multidisciplinary research program that will put Stanford at the forefront of the cancer stem cell field.

Pathways to cancer

Beachy didn't start out studying either cancer or stem cells. Instead he received his PhD in biochemistry from Stanford, where he studied the early development of fruitflies. That work led him to focus on the role of a protein called Hedgehog in the developing fly. He has since become one of the foremost experts—along with Matthew Scott, PhD, professor of developmental biology—in understanding how the Hedgehog protein signals cells during the fetal development of such animals as flies, mice and humans. The protein plays a critical role in telling cells where they are in the body and what type of tissue they should become.

As that work progressed during his 18-year career at Johns Hopkins, Beachy realized that the Hedgehog protein signaling pathway also had a role in cancer. Some of his colleagues, including Scott, had studied mutations in genes coding for proteins that interact with Hedgehog; the researchers found that people with those mutations were at greater risk for several cancers. Beachy found that a drug known to inhibit Hedgehog protein successfully reduced the size of brain tumors in a lab dish and in mice. In later lab experiments, that same drug effectively inhibited the growth of cells from cancers of the lung, gastrointestinal tract and prostate. Several pharmaceutical companies are now exploring the use of such drugs to treat human cancers.

Hedgehog appears to encourage the cancer stem cell to churn out new cancer cells. Another protein that plays a similar role in some cancer stem cells is Wnt (pronounced "wint"), which is the domain of Roel Nusse, PhD, professor of developmental biology and an expert in Wnt signaling. "Hedgehog and Wnt are really sister pathways that may be fairly fundamental in many types of cancer," said Beachy, who is also a Howard Hughes Medical Institute investigator.

Weissman said that work by Beachy, Scott and Nusse dissecting how Wnt, Hedgehog and other proteins maintain cancer and leukemia stem cells could result in drugs that interfere with those pathways, eliminating those cells.

If such drugs do come out of their research, both Weissman and Beverly Mitchell, MD, cancer center deputy director, want to have the trials also take place here to benefit Stanford patients.

Beachy shares that goal. One of the reasons he chose to move to Stanford is its emphasis on basic research that could yield new therapeutic approaches, in addition to the chance to work with other experts in his field.

On track off-campus

At the stem cell institute's lab space off the main campus on Arastradero Road in Palo Alto, a group of about 20 researchers from the Weissman and Clarke labs are following another track in the quest to better understand cancer stem cells. They are hunting for stem cells in bladder, colon, head/neck, ovarian and some blood cancers.

The idea of cancer stem cells goes back to 1950s but didn't become generally accepted until 1994 when John Dick, PhD, at the University of Toronto published the first paper identifying a cancer stem cell in leukemia. Such cells have now been found in breast, brain, prostate and some blood cancers.

The process of identifying the cancer stem cells follows on the groundbreaking work by Weissman to isolate adult stem cells of the blood and brain. Both rely on the fluorescence-activated cell sorter, developed by Kyoto Prize winner Leonard Herzenberg, PhD, professor of genetics, and his Stanford engineering colleagues. Researchers use the FACS to pool cancer cells from tumor samples according to proteins on their surfaces. They then transplant isolated groups of cells into mice to see which ones form human tumors in the mouse hosts. Most of the cells divide briefly then fizzle out. Cells from just one pool—the ones that turn out to be cancer stem cells—slowly build up the supply of cancer cells, forming new human cancers in the mouse.

This approach has the advantage of both finding the cancer stem cell and providing an avenue for therapy. Those cell surface proteins that act as a molecular name tag for the cancer stem cell could also be a way of targeting the cells for destruction. Research groups at Stanford and elsewhere are looking for drugs that home in on those proteins or other proteins within the cell to destroy the cancer. Other groups are finding ways of tricking the body's own immune system into attacking the proteins and eliminating the cells.

Horse out of the barn

While Beachy and others learn more about what makes cancer stem cells tick, Clarke is taking the work in a different direction. He is collaborating with Pat Brown, PhD, professor of biochemistry, to learn how to identify which cancer stem cells form the most aggressive types of cancers. They are looking at which genes are active in the cancer stem cells of many cancer patients and comparing that with how well those patients responded to treatment. They hope this process will reveal a group of genes that are active in stem cells of cancers that either do or do not respond to chemotherapy. That information could help surgeons decide which tumors need surgery and which might respond to less-aggressive measures.

Clarke has teamed up with Andrew Shelton, MD, a colon cancer surgeon, to put cancer stem cell research into practice. Shelton hopes to use Clarke's data to prevent surgery for patients who don't need it. "People who have a colostomy have to wear a colostomy bag for life," Clarke said. "We would like to avoid that surgery if it's not needed."

This is just the first of what Weissman hopes will be many collaborations between stem cell researchers and clinicians. He thinks Beachy's arrival will help drive even more efforts to translate the basic science into treatments for patients, both in cancer and other areas of stem cell research. "His work is relevant to everything we are doing in stem cell research," Weissman said.

Despite the enthusiasm at Stanford and elsewhere, some critics remain unconvinced that these cells will be a panacea. Harvard oncologist William Hahn described himself as a "skeptical observer who likes the idea of cancer stem cells," in a recent Nature news story. He and others point to the lack of detailed molecular knowledge about cancer stem cells and previous hype over cancer strategies that failed to pan out in trials as reasons for their hesitation.

These concerns leave Weissman unmoved. "The horse is out of the barn on cancer stem cells," he said. He thinks skeptics are missing out on what will be the hottest field in cancer research.