(continued from page 2)
Both normal stem cells and progenitor cells, because of their long-lived natures – stem cells could be around for an entire lifetime – have the potential to accumulate the multiple mutations required for carcinogenesis. The hypothesis is appealing as an explanation for how tissues with very short-lived mature cells, like the blood, skin, and lining of the gut, can accumulate enough mutations to give rise to
a tumor: the mutations happen in the long-lived stem/progenitor
cell population.
A cancer stem cell can be thought of as lurking in the general stem cell population, Kasper explains. Once it has accumulated a number of mutations, it’s there “waiting for the right stimulus to activate it so that it begins proliferating.
“No one knows what those signals are – we talk about cancer stem cells and how they might work, but very little is known about the biology of cancer stem cells,” she says. “For example, how do these cells arise? How do they survive and proliferate? Is the core of
a metastatic lesion a cancer stem cell?”
Kasper and colleagues have developed human prostate cancer stem cell lines (cells that can be grown in the laboratory indefinitely) that they will use to address these kinds of questions.
Are cancer treatments off target?
The cancer stem cell hypothesis, if correct, could explain why many cancer treatments don’t improve long-term patient survival. Treatments are selected for their ability to cause tumor shrinkage, which doesn’t necessarily predict improved survival.
“We’ve basically designed a lot of treatments that kill the wrong cells in the tumor,” Wicha says. “The treatments leave the cancer stem cells behind, and those cause recurrence.”
Wicha cites evidence from animal models and from ongoing studies in patients with breast and pancreatic cancer. He and colleagues have examined the cells that remain after chemotherapy and radiation therapy shrink the tumors.
“If you transfer those cells that are left to a mouse, they grow like crazy,” he says.
Cancer stem cells may be more resistant to cancer treatments because of the properties they share with normal stem cells: slow cell division cycles (cancer therapies often target rapidly dividing cells) and high levels of proteins that protect against DNA damage and cell death.
These shared properties may also lead to the development of novel therapies that act across many different tumor types. Signaling pathways that are important for normal stem cells during development, such as the Wnt, Hedgehog and Notch pathways, also appear to be important regulators of cancer cell growth.
“What we learn about one cancer stem cell in one kind of tumor is informing us about what’s going on in another kind of cancer stem cell,” Wicha says. “If we develop an effective therapy for one kind of cancer – and that’s a big if – it might be effective in killing stem cells in another cancer too.”
Clinical trials of existing drugs or unique combinations of drugs that target surface proteins on cancer stem cells are already ongoing for multiple myeloma and leukemias.
And Wicha and colleagues at the University of Michigan, along with investigators at the Dana-Farber Cancer Center and Baylor College of Medicine, are gearing up for the first clinical trial targeting cancer stem cells in a solid cancer. The trial will test an inhibitor of the Notch signaling pathway in breast cancer. The drug, developed by Merck, kills breast cancer stem cells in laboratory studies.
The ultimate test: survival
Clinical trials of cancer stem cell-directed therapies face challenges. Will the treatments kill normal stem cells that are important for tissue maintenance and regeneration? What are the measures of success for a treatment that’s directed against a tumor’s slow-growing “roots” rather than its visible “weed?”
The potential for killing normal stem cells is perhaps the biggest challenge to the field, Wicha says. There are data now being published that support the notion that cancer stem cells may have different sensitivities to certain drugs, even though the drugs target pathways that are also active in normal stem cells.
“The extra mutations in the cancer stem cell may make it particularly vulnerable to certain kinds of treatment that don’t affect a normal stem cell,” Wicha says. “That remains to be proven. The real test will be in giving these agents to patients; we’ll be watching very carefully for side effects.”
Tumor shrinkage is a traditional measure of success for cancer therapies. But cancer stem cell-targeted treatments may not have any visible effects on the bulk of a tumor. One notion is to first use another agent to “de-bulk” the tumor and induce remission, and then follow with a cancer stem cell-targeted agent, using duration
of remission as a measure of success. Investigators are also exploring alternate laboratory-based tests.
Ultimately, the question is – are cancer stem cells truly the cells that regenerate the tumor, and if they are killed, does that eliminate the cancer and improve survival?
Measuring survival takes a long time, which is why investigators are designing alternate tests. They will eventually have to prove that these quicker measures “correlate with patients living longer – that’s the ultimate test for any therapy,” Wicha says.
“I hope that people won’t get discouraged if the first trials don’t work,” he adds. “We’re really just at the beginning of this, and I think the idea is right.”
Roundup, anyone? 
Learn more about Vanderbilt’s Center for Stem Cell Biology at www.vcscb.org.
|
