A standard chemotherapy drug may make a small but aggressive population of brain cancer cells even more deadly, a study in the March 6 Cell Stem Cell reports. Understanding how these cells turn dangerous may ultimately lead to better ways to destroy brain tumors.

“This really shows how important it is that we have therapies against different populations of cells,” says Anders Persson of the University of California, San Francisco, who coauthored a commentary in the same issue of Cell Stem Cell. “You can’t just give one treatment and think it will kill every cell.”

The most common cancer originating in adults’ brains — glioblastoma multiforme — is particularly complex and notoriously resistant to standard treatments. The resistance may be caused by small numbers of cancer cells called side populations, says Eric Holland, a neurosurgeon at Memorial Sloan-Kettering Cancer Center in New York City and coauthor of the new study.

The new study finds that these side population cells make up only 4 to 8 percent of all cells of a mouse brain tumor. And the cells may be able to produce multiple types of cancerous cells with different properties and rebuild the entire tumor from the ground up, like the noncancerous stem cells that can create entire organs.

Currently, a drug called temozolomide is the first-line treatment for glioblastoma in humans. When brain tumors are treated with temozolomide, many cancerous cells die, but the side populations live on in greater numbers, the new study shows. When treated with the drug, side populations of mouse cancer cells grew to make up as much as 30 percent of all cancerous cells, Holland and his team found.

When researchers applied temozolomide to mouse cancer cells lacking a known cancer-preventing gene PTEN, the side population cells made up 75 percent of all cancer cells. 

The new work supports the idea that “the treatment we throw at tumors” affects these small but dangerous populations of cancer cells, comments William Weiss, a neurologist at the University of California, San Francisco who coauthored the Cell Stem Cell commentary.

The researchers also tested temozolomide’s effects on how quickly tumors from side populations grow. On average, tumors formed after 25 days in cancer-free mice that were implanted with temozolomide-treated side population cells, while untreated cells took more than 40 days to grow into tumors.

Temozolomide may select for the most aggressive of the already aggressive side population cells, Holland suggests.

“The few cells that survive come roaring back and kill the patient.” But he does not advocate changing treatments: “It’s very clear that with temozolomide, patients survive longer.”

Whether these side populations of cancer cells are truly stem cells, with the capacity to grow back a complex cancer, is still unclear. The notion is “a very attractive hypothesis” that may help explain why chemotherapy treatments don’t always cure cancer, says Weiss.

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