Evidence Grows That Cancer Has Its Own Stem Cells

While scientists hotly debate the existence of cancer stem cells, three related new studies, all conducted on mice, provide some supporting evidence.

Stem cells are the foundation for healthy cell growth in the body. Some researchers believe that malignant stem cells also exist — so-called cancer stem cells that generate tumors and resist treatment by simply re-growing afterward.

“Cancer stem cells are still controversial, but with progress in studies like these, it’s less about whether they exist and more about ‘what does this mean?'” said Dr. Max Wicha, director of the University of Michigan Comprehensive Cancer Center, who is familiar with the new findings.

Appearing online Aug. 1 in the journal Nature, one study involved mice with glioblastoma, the most common malignant brain tumor in adults and a particularly lethal cancer.

Researchers led by Luis Parada, a professor and chairman of developmental biology at University of Texas Southwestern Medical Center in Dallas, genetically engineered mice so they would develop glioblastoma.

Then they developed a “transgene” designed only to be active in stem cells in healthy adult brains. They marked this transgene with a green fluorescent protein so the researchers would see it wherever it appeared.

To this transgene they added a virus gene that would self-destruct if treated with the drug acyclovir.

Next, they put the transgene into the mice, which developed tumors. In every mouse, a subset of cells in the malignant brain tumor cells was green.

“The next obvious question was: Since the ‘transgene’ was designed to be active in stem cells, might these be stem cells?” Parada said.

The researchers gave the drug acyclovir to mice that had tumors. “And when we did that, the tumors stopped growing,” he said.

The investigators also looked at “regular” cancer cells and found that those cells were not green. And while tumor cells divided, the green cells rested.

“That observation was reminiscent of a normal stem cell environment,” Parada said. “If we go back to adult stem cells, the stem cells are mostly quiescent. That means they rarely divide.”

In healthy brain tissue, he said, a few stem cells eventually enter the cell cycle, and give rise to progenitor cells that divide frequently before becoming neurons in the brain. The researchers wanted to show that cancer cells had a similar cycle.

Their next experiment was to apply the chemotherapy drug temozolomide to the tumor-ridden mice, which got rid of all the currently dividing tumor cells. But when the chemotherapy stopped, the tumors resumed cell division.

The cells not eradicated — that were still giving rise to new cancer cells — were the specially marked green cells that behave similarly to stem cells in healthy tissues.

In a final experiment, “we were able to give the mice temozolomide to get rid of the highly dividing cells, plus ganciclovir to get rid of the stem cells. And when we did that, the tumors were unable to form,” Parada said.

Just what are the implications for human cancer?

“With a solid tumor that’s formed by cancer stem cells in a hierarchical fashion, the critical cells to identify, understand and target with chemotherapy are the cancer stem cells,” he said.

The research is still in early stages, Parada noted. “Now, knowing that these cells exist and being able to identify them inside of the tumors, we’re trying to isolate them, purify them and study them in great detail,” he added.

His caveat: Their work with glioblastoma may not apply to different kinds of cancers. “Each cancer has to be studied in this same way to determine if the cancers grow in this fashion or not,” Parada said.

A second study in the same Nature issue investigated the growth of squamous skin cancer. By marking and tracing individual tumor cells in mice, researchers at the Free University of Brussels found a subset of tumor cells with properties similar to stem cells in normal tissue.

Meanwhile, a Dutch team looked at mouse intestinal tumors. In that study, published online Aug. 1 in the journal Science, researchers at University Medical Center Utrecht also found signs of what might be cancer stem cells.

However, scientists note that research with animals often fails to provide similar results in humans.

“It’s interesting that all the studies came to the same conclusion with different types of cancer,” said Wicha. “All use very elegant molecular tracing studies in mice.”

Whereas previous studies were criticized for transplanting tumors from other sources into the mice being studied, he said these studies had the advantage of looking at the tumors in their natural environment.

Wicha said early clinical studies are already under way, using new drugs to directly target the cancer stem cells.

More information

Visit the U.S. National Cancer Institute to learn more about glioblastoma.

SOURCES: Luis F. Parada, Ph.D., professor and chairman of developmental biology, University of Texas Southwestern Medical Center, Dallas; Max S. Wicha, M.D., director, University of Michigan Comprehensive Cancer Center; Aug. 1, 2012, Nature, online; Aug. 1, 2012, Science, online