Not too long ago, the idea that stem cells could give rise to tumors was only a theory. The hypothesis was that cancer stem cells had the unique ability to evade the lethal effects of radiation and chemotherapy because those treatments target rapidly dividing cells.

Cancer stem cells, however, could lay dormant, recur and spread, making the cancer difficult to cure. Today, mounting evidence supports that theory. UC Davis researchers are among those looking for cancer stem cells and working on ways to destroy them. Their work offers new hope for curing some of the deadliest forms of the disease, says Jan Nolta, director of the UC Davis Stem Cell Program.

"We now have clear evidence that some types of tumors arise from a stem cell that has gone awry," Nolta says. Scientists are starting to view cancer as a stem cell differentiation disease, she says. "Until we understand the nature of cancer stem cells, we can't stop the recurrence."

Since scientists discovered leukemia cancer stem cells in 1997, cancer stem cells have been found in brain, breast, colon, ovarian, pancreatic and prostate cancers.

Normal stem cells have the capacity to self-renew and differentiate into a number of cell types. Self-renewal means dividing into two daughter cells: one identical to itself and one that will differentiate into a specific tissue. With cancer stem cells, this process is not well understood, and normal differentiation may be blocked. Those that self-renew may be the cells that spread to different sites, a process called metastasis.

Nolta's lab acts as a clearinghouse for many UC Davis cancer researchers. She and her colleagues isolate stem cells from tumors and other tissue samples, providing them to different groups on campus. "These groups have state-of-the-art tools for asking the important questions about cancer stem cells that will one day let us wipe them out," she says.

Bladder cancer

The questions UC Davis researchers are asking depend on what type of cancer they are studying and how well its basic biology is understood. Eric Kurzrock is an associate professor of urology and pediatrics who treats children in the clinic and operating room, but studies bladder stem cells in the lab. He says that about 10 to 20 percent of bladder cancers are aggressive, possibly due to dormant bladder cancer stem cells that are able to evade otherwise effective treatment.

Kurzrock not only is searching for those cells, but also is studying human embryonic stem cells. He hopes to prod human embryonic stem cells into differentiating into the cells that line the bladder, called urothelial cells, because they are the ones that eventually become cancerous.

"Once we understand normal differentiation, then we can understand abnormal differentiation – which is the definition of cancer," says Kurzrock, one of a few researchers in the country looking for bladder cancer stem cells. "We think a lot of cancers come from mutations in stem cells, and bladder cancer is likely one of them."

Brain cancer

Mutated stem cells are now thought to be behind one of the deadliest cancers, a form of brain cancer called glioblastoma multiforme. According to the National Cancer Institute, the five-year survival rate for glioblastoma is only 3 percent. Removal of the tumor in most cases does little to improve prognosis as the tumors readily grow again.

In 2007, a team of UC Davis researchers led by assistant professor of neurosurgery Rudolph Schrot was the first to identify the specific location of cancer stem cells within human brain tissues from a glioblastoma patient. Their findings were published in the Journal of Neuro-Oncology. Since then, Joyce Ma, an M.D.-Ph.D. student and co-author of the paper, has developed a new therapeutic agent that targets these brain cancer stem cells while sparing normal cells. She is working with Nolta to test the treatment in the lab.

"Chemotherapy and radiation cannot tell the difference between cancer cells and normal cells," Ma explains. "Our therapeutic agent seeks out cancer stem cells and causes them to die in a way that doesn't injure the surrounding tissue." Ma hopes to prevent tumor recurrence while reducing the side effects associated with current cancer treatments.

Breast cancer

Scientists discovered breast cancer stem cells in invasive cancer in 2003. UC Davis professor of radiation oncology Jian-Jian "JJ" Li is working to understand how invasive breast cancer stem cells become resistant to radiation therapy.

"We are the first to show that breast cancer cells that are initially susceptible to radiation undergo changes during treatment so that they become resistant to treatment," explains Li, who also is director of translational research for the Department of Radiation Oncology.

Li's work focuses on a particular kind of invasive cancer called HER2- negative breast cancer. HER2 stands for human epidermal growth factor receptor-2. Approximately 15 to 20 percent of breast cancer tumors test positive for this cell-surface protein. It is associated with increased disease recurrence and worse prognoses, and is treated with a drug (trastuzumab, marketed as Herceptin) that targets those cells.

Li's work showed that HER2- negative breast cancers can become HER2-positive during radiation treatment. He is focused on targeting these radiotherapy-resistant cells. "If we can do that, we can tremendously improve the efficacy of breast cancer treatment," he says.

Cells that cause invasive breast cancer in humans most likely arise as precancerous stem cells found in milk ducts, a team led by Alexander Borowsky reported in Breast Cancer Research last year. "Our work shows that programmed cancer stem cells are already present at the earliest stage of breast cancer," says Borowsky, an associate professor of pathology and laboratory medicine, who holds a joint appointment at the UC Davis Center for Comparative Medicine.

This early form of breast cancer is called DCIS, or ductal carcinoma in situ. In DCIS, abnormal cells multiply and form a growth within a milk duct of the breast. DCIS is noninvasive and is usually easily treated with breast-conserving surgery and radiation. If it is not completely treated, however, it may give rise to potentially lethal invasive breast cancer, which infiltrates surrounding breast tissue and can metastasize to other parts of the body.

Borowsky did his work in mice, first by developing the mouse model of human DCIS. The mice reveal that breast cancer outcomes can be programmed in the pre-cancer stem cells. He is now working to use breast cancer stem cells collected from DCIS biopsies as diagnostic tools to predict cancer behavior and eventually to tailor therapies to improve patient outcomes.

"Detection of DCIS by improved imaging technology is rapidly increasing," he says. "Some of these women whose breast cancer is caught in this earliest stage may be better treated with drug or hormonal therapy, whereas others may need more aggressive surgical and radiation treatment."

Leukemia

Leukemia cancer stem cells were the first cells to be studied, yet the science to target them is almost futuristic in nature. Chong-Xian Pan and his colleagues are developing tiny guided missiles that seek out and destroy leukemia stem cells. The work involves creating ligands, which are molecules that recognize and bind to proteins on leukemia stem cells. These ligands are attached to nanoparticles, man-made objects tiny enough to enter a cell, carrying lethal chemotherapy drugs.

"Inside the nanoparticles we can load chemotherapy drugs, allowing us to deliver high concentrations of the drugs directly to the cancer stem cells," Pan says. Researchers already know these drugs work and, at the highest doses, they work even better. Those high doses, however, are quite toxic to patients.

"These nanoparticles will allow us to use those high doses on just the cancer stem cells, sparing the patient of severe side effects and eliminating the cancer." Pan and his colleagues are testing these therapies on animal models and human leukemia cancer cells in culture.

Pan believes most researchers no longer question the existence of cancer stem cells. "We think cancer stem cells are possibly a universal phenomenon for most cancer types," he says.

Definition debate

Controversy remains, however, on how to define them. According to Borowsky, a cancer stem cell must have the self-renewal and differentiation properties of normal stem cells and the ability to reconstitute a cancer when transplanted from one animal to another in the lab. Some researchers are using markers found on other cancer stem cells for identification purposes, but only animal transplant studies offer definitive proof.

"Markers are only surrogates," Borowsky says, adding that it's more likely that some cancers would have stem cells with a different array of markers, as he has found in mice. "I think it's safe to say that defining the markers still remains a challenge."

Still, Borowsky says, the effectiveness of new cancer therapies will be measured by how well they kill stem cells. "All treatments probably affect cancer stem cells to some extent, but identifying the rate of cancer stem cell death is going to be an important thing to know."