Clever Stem Cells Withstand Chemo Drug’s Harmful Side Effects

For some conditions, it seem that the treatment can cause almost as many problems as than the disease itself. That’s often the case with some forms of cancer, such as acute lymphoblastic leukemia.

The most common type of cancer to affect children, treatment usually involves chemotherapy with the drug methotrexate (MTX). And, while effective at destroying the deadly cancer cells circulating in the patients’ blood, it also does significant damage to another part of the body: the bone.

But new research from Brown University’s Dr. Eric Darling and his team has found that not all types of bone cells are equally at risk of being damaged by MTX. In fact, one type may actually be impervious to the drug’s negative effects. These findings, published last week in the journal Experimental Cell Research, are especially important as doctors look to ways that help the youngest, most vulnerable cancer patients heal faster after treatment—regaining bone strength that can take them into a healthy adulthood.

As Olivia Beane, a graduate student in the Darling Lab and the lead author of this paper, explained in a news release:

“Kids undergo chemotherapy at such an important time when they should be growing, but instead they are introduced to this very harsh environment where bone cells are damaged with these drugs. If we found a stem cell that was resistant to the chemotherapeutic agent and could promote bone growth by becoming bone itself, then maybe they wouldn’t have these issues.”

The cell type Beane is referring to are called adipose-derived stem cells, or ASCs, which normally mature from this early, stem cell state into several types of mature cells, including bone tissue. Initially, Beane had been researching the basic properties of ASCs. But during her experiments she discovered that ASCs, unlike other stem cell types that mature into bone, appear to survive MTX. Now they just needed to understand why.

Further experiments revealed the underlying strengths of ASCs in resisting MTX’s effects. Normally, MTX works by binding to and shutting down a protein in the cell called dihydrofolate reductase, which is normally involved in synthesizing DNA. With DNA production shut down, cells can’t divide and multiply—which is great for killing harmful cancer cells, but potentially harmful as it can also destroy cells it shouldn’t.

However, ASCs are a little bit different. When coming into contact with MTX, these cells ramp up the DNA-promoting dihydrofolate reductase, producing more than enough to overcome a normal dose of MTX.

This discovery has raised some intriguing possibilities for treating MTX’s side effects. As Darling explained:

“Chemotherapies do a great job of killing cells and killing the cancer, and that’s what you want. But then there is a stage after that where you need to do recovery and regeneration.”

And while the results of this study are preliminary, the researchers are cautiously optimistic that the MTX-resistant properties of ASCs could be the key to fast tracking recovery times.

The first step, Darling adds, is to save a life. And MTX has done that for countless children afflicted by cancer. But the cost of saving that life should also be taken into account—so that these children who have already been through so much may one day not need to worry about long, healthy lives as they mature into adults.

Want to learn more about how CIRM-funded researchers are developing new tools to fight all types of leukemia? Check out our Leukemia Fact Sheet.

Anne Holden