Killing Cancer Stem Cells

A new screening method identifies drugs that selectively target these elusive cells in tumors.

Recent evidence suggests that certain cancers may persist or recur after treatment because a small population of cells, called cancer stem cells, remains behind to seed new tumors. Though scientists are not yet certain about the role cancer stem cells play in disease, evidence is accumulating that these cells are particularly resistant to chemotherapy and radiation, and can linger in the body even after treatment.

Cell attack: Cancer cells in tumors treated with salinomycin–a drug that specifically targets cancer stem cells–have a less malignant appearance (right) and look more like differentiated cells than untreated cells (left).

Several research groups have begun looking for substances that kill these cells. A new approach, developed by researchers at the Whitehead Institute for Biomedical Research and the Broad Institute of MIT and Harvard, makes use of high-throughput screening methods to identify chemicals that selectively target these elusive cells. In a study published today in Cell, the researchers identify one particular drug that kills breast cancer stem cells in mice. Although it is still unclear whether the drug will be useful in humans, the researchers believe their study demonstrates that it’s possible to target these cells selectively.

Because cancer stem cells, which have the ability to give rise to new tumors, may remain behind after chemotherapy and radiation treatments, finding ways to target these cells specifically may offer a way to make treatment more effective. But accessing and studying cancer stem cells has been challenging because very few are present in tumors and they are difficult to generate and maintain outside the body. Other groups have recently screened for drugs that target leukemia stem cells and brain cancer stem cells. In the Cell paper, a team led by the labs of Eric Lander at the Broad Institute and Robert Weinberg at the Whitehead Institute developed a way to generate a large number of cells that mimic naturally occurring epithelial cancer stem cells; these cells can be maintained in this state for long periods of time.

Epithelial cancers are the most common types of cancer in adults and affect the skin and inner lining of organs in the body. Using epithelial breast cancer cells, the researchers introduced a genetic change in these cells, causing them to take on the properties of mesenchymal cells, which form connective tissue in the body. Piyush Gupta, a co-author at the Broad Institute, says that for reasons not completely known, when this “epithelial-to-mesenchymal transition” is performed on breast cancer cells, it promotes the development of a large number of cells that he says are “indistinguishable from cancer stem cells.” These cells can then be grown in tiny pockets on plates and screened robotically for their response to large collections of chemicals.

The researchers used a library of 16,000 chemicals at the Broad Institute to look for compounds that killed these transformed breast cancer stem cells more effectively than they killed normal breast cancer cells. Gupta explains that since cancer stem cells are usually resistant to drugs, relatively few chemicals are effective–a mere 32 compounds were identified in the screen as preferentially treating breast cancer stem cells.

After some initial testing of several compounds, the researchers focused on one drug called salinomycin. They compared it to the actions of a drug commonly given in breast cancer chemotherapy, paclitaxel (also known by its brand name, Taxol), in cultured cells and in mice. While paclitaxel treatment leads to a higher proportion of drug-resistant cancer stem cells, salinomycin had the opposite effect, reducing the number of breast cancer stem cells in cultured cells more than 100 times more effectively than paclitaxel. The drug also reduced breast tumor growth in mice, although the reduction was less dramatic.

Gupta says that it’s not clear whether salinomycin will be a clinically useful drug, because it has not yet been tested in humans. The team is continuing to study this initial candidate drug, but he also notes, “we’re following up on several others that we think may be promising.”

Jeffrey Rosen, a breast cancer researcher at Baylor College of Medicine, in Houston, TX, says that the study is an early example of a promising new turn in the hunt for cancer therapies. “It’s very exciting that some groups are starting not to view tumors as homogeneous entities but to target subpopulations of cells we think are import for drug resistance,” he says. However, Rosen notes that the results in mice were not as promising as the drug’s performance in cells. He says that the cancer field is hampered by a lack of good animal models to determine which drugs will be relevant for therapies. The problem, he says, is “once you pull out a compound or drug, then how do you actually go the next step and show that it’s really going to work?”

Weinberg calls the study “the first step in the direction of trying to eliminate these cells in tumors.” He believes that even if the role of cancer stem cells in different kinds of cancer has not been resolved, “we have no doubt that getting rid of them is going to be an important part of creating cures.”

Although this study focused on breast cancer, the researchers anticipate that the screen could be applied to any kind of epithelial cancer. Gupta says that while targeting cancer stem cells may not necessarily be a “magic bullet” in cancer treatment, “if you have a certain subpopulation of cancer cells that are resistant to standard treatment, you would want to find a compound that targets these cells.” He adds that a drug that targets cancer stem cells could be used in combination with standard treatments to ensure that resistant cells are not left behind.

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