Researchers have developed a new method to look at the effects of chemotherapies on cancer stem cells. Through screening cancer drugs in fruit flies, they have demonstrated that a number of chemotherapy drugs, while they kill cancer cells, actually induced normal stem cells to divide more rapidly.

Such rapid division of normal stem cells can itself contribute to cancer development.

The results, which were published in the March 10, 2014, advance online edition of the Proceedings of the National Academy of Sciences, suggest that chemotherapies may be indirectly contributing to recurrence of the tumors they are supposed to fight.

Corresponding author Michele Markstein, who is at the University of Massachusetts at Amherst, stressed that although they do point toward certain drug combinations as prudent, her team’s results should not be interpreted to mean that chemotherapies cause cancer.

The development of cancer, she told BioWorld Today, “is a multistep process.”

But they do show that chemotherapy can induce “one step in that multistep process that could lead to cancer,” a finding that she called “troubling.”

Markstein and her team used an unusual experimental model to arrive at their conclusions: drosophila melanogaster or the fruit fly.

Many experiments probing the molecular basis of cancer are done in cell culture, while the most popular animal model is the mouse.

But Markstein said that drosophila has its own strength is being a very simple animal model, but still a whole animal model.

Researchers are increasingly bumping up against the limitations of using cell lines, because the development and progression of tumors is intricately linked to their interaction with the microenvironment.

Using whole animals allows those microenvironments to be preserved. The approach is conceptually similar, in a way, to the development of 3-D cell cultures and organoids. (See BioWorld Today, Dec. 13, 2013, and April 10, 2013.)

In fact, Markstein said, “You can think of the fly as an organoid that is consistent from well to well, and that has the physiology all balanced, at least for a fly.”

As for using flies instead of mice, Markstein said that “what you can’t do in mice is drug screening in large numbers.” In the experiments now published in PNAS, Markstein and her colleagues screened 60,000 flies.

And “the stem cells in the intestine are remarkably similar between flies and mice. More so than you might think. . . . Given that the biology is so well conserved, it makes sense to use them as a model.”

For their paper, “we pioneered a lot of methods to develop drug screening in flies,” ultimately enabling them to have flies live in the wells of a 96-well plate, where they could be fed chemotherapy drugs and analyzed en masse.

The team used those methods to compare the effects of chemotherapy drugs on two different types of cells, namely, regular intestinal stem cells, and those that had a transgene engineered into them to turn them into rapidly dividing cancer stem cells.

Both stem cells in general and cancer stem cells are resistant to many chemotherapies, but Markstein and her team assumed that the rapidly dividing cancer stem cells would be susceptible to at least some chemotherapies. And in a screen of nearly 90 FDA-approved chemotherapies, they indeed found slightly more than a dozen that affected cancer stem cells.

But to their surprise, the researchers also saw an effect of some drugs against regular stem cells.

Markstein said she expected the chemotherapies to show “no effect” against regular stem cells. But instead, about half the drugs that were effective against cancer stem cells also induced regular intestinal stem cells to divide more rapidly.

The effect was due to inflammatory signals from the microenvironment, confirming Markstein’s assertion that looking at cells within their interactions with other cells is important for understanding their behavior. “It is important to study these drugs in whole animals, and our results shows that flies work,” she said.

Markstein and her colleagues are working on two broad questions brought up by their research. For one thing, it is not obvious why stem cells are able to resist chemotherapies, especially if those chemotherapies are inducing them to proliferate – since chemotherapies target rapidly dividing cells.

The team is also using the methods it developed to look at the effect of environmental toxins on tumors and stem cells, and colleagues are testing whether the model can be useful to study other types of stem cells, such as neural stem cells.

Markstein pointed out that although the effects that she and her colleagues uncovered were somewhat worrisome, the methods they used to detect them could also uncover beneficial effects of the microenvironment.

“Powerful drugs may be found that don’t directly inhibit stem cell cancers, but that do so indirectly by the microenvironment,” she said. “Whole animal screens could allow us to find these kinds of drugs.”