Reprogramming Stem Cells May Suppress Cancer after Radiotherapy

The body has developed strategies of purging defective stem cells. A new study has revealed that one of these ways is a “program” that makes stem cells damaged by radiation differentiate into other cells that can no longer survive forever.

Radiation makes a stem cell lose its “stemness,” which makes sense because damaged stem cells do not need to hang around to pump out damaged cells. Moreover, the research, conducted by University of Colorado (CU) Cancer Center (Aurora, USA) scientists, and published online December 27, 2014, in the journal Stem Cells, demonstrated that this same protection of “programmed mediocrity” that rids stem cells damaged by radiation allows blood cancers to grow in instances when the total body is irradiated. Furthermore, by reprogramming this defense, cancer may be prevented in the aftermath of full body radiation. “The body didn’t evolve to deal with leaking nuclear reactors and CT scans. It evolved to deal with only a few cells at a time receiving dangerous doses of radiation or other insults to their DNA,” said James DeGregori, PhD, investigator at the CU Cancer Center, professor of biochemistry and molecular genetics at the CU School of Medicine, and the article’s senior author.

Dr. DeGregori, doctoral student Courtney Fleenor, and colleagues examined the effects of full body radiation on the blood stem cells of mice. In this case, radiation increased the probability that cells in the hematopoietic stem cell system would differentiate. Only, while most obeyed this instruction, a few did not. Stem cells with a very specific mutation were able to disobey the instruction to differentiate and retain their “stemness.” Genetic inhibition of the gene C/EBPA allowed a few stem cells to keep the ability to act as stem cells. With competition from other, healthy stem cells removed, the stem cells with reduced C/EBPA were able to dominate the blood cell production system. In this way, the blood system transitioned from C/EBPA+ cells to primarily C/EBPA- cells.

Mutations and other genetic alterations resulting in inhibition of the C/EBPA gene are associated with acute myeloid leukemia in humans. Thus, it's not mutations caused by radiation but a blood system reengineered by faulty stem cells that creates cancer risk in people who have experienced radiation. “It’s about evolution driven by natural selection,” Dr. DeGregori noted. “In a healthy blood system, healthy stem cells out-compete stem cells that happen to have the C/EBPA mutation. But when radiation reduces the heath and robustness of the stem cell population, the mutated cells that have been there all along are suddenly given the opportunity to take over.”

These studies do not only clarify why radiation makes hematopoietic stem cells (HSCs) differentiate; they also show that by activating a stem cell maintenance pathway, we can keep it from happening. Even months after irradiation, artificially activating the NOTCH signaling pathway of irradiated HSCs lets them act “stemmy” again—restarting the blood cell assembly line in these HSCs that would have otherwise differentiated in response to radiation.

When Drs. DeGregori, Fleenor and colleagues triggered NOTCH in earlier irradiated HSCs, it kept the population of dangerous, C/EBPA cells at bay. Competition from non-C/EBPA-mutant stem cells, with their health restored by NOTCH activation, meant that there was no evolutionary space for C/EBPA-mutant stem cells.

“If I were working in a situation in which I was likely to experience full-body radiation, I would freeze a bunch of my HSCs,” Dr. DeGregori stated, explaining that an infusion of healthy HSCs after radiation exposure would likely allow the healthy blood system to out-compete the radiation-exposed HSC with their ‘programmed mediocrity’ [increased differentiation] and even HSC with cancer-causing mutations. “But there’s also hope that in the future, we could offer drugs that would restore the fitness of stem cells left over after radiation.”

Related Links:
University of Colorado Cancer Center