Possible Source of Pediatric Cancer Identified

Tumors are most often developed through decades of accumulating genetic errors, which is why their presence in young children has long baffled scientists. However, in a new study published in the Proceedings of the National Academy of Sciences, researchers have identified what they believe is a missing piece to the pediatric cancer puzzle.

Normal, healthy cells contain checkpoints that prompt cells to repair damaged DNA before replicating. Cancer cells, many researchers believe, flourish when these checkpoints are somehow skipped or inhibited, leaving mutated cells to survive and reproduce rapidly. As these cells collect, tumors are formed, leading to many childhood cancers, such as rhabdomyosarcoma, neuroblastoma and osteosarcoma.

In the new study, however, scientists found that dampening a specific feedback loop between a repair checkpoint and its controlling pathways may promote the growth of such tumors.

"Our prior studies had shown that the DNA damage checkpoint protein, ATM, was very low in most pediatric solid tumors," Dr. Peter Houghton, a faculty member at the Ohio State University College of Medicine, said in a press release. "The question was why?"

Their research showed that a number of problems could be at play in the development of pediatric tumors.

One of these includes a pathway called mTOR, which regulates the production of a cancer-causing gene that tells the cell to produce too much of two kinds of microRNAs. As a result, these microRNAs suppress the synthesis of ATM, making it difficult for cells to initiate the damage checkpoint.

Low levels of ATM then allow the mTOR pathway to keep producing the microRNAs that further reduce the ATM-mediated checkpoint activity. And when the microRNAs weaken the cell's damage checkpoint, the checkpoint cannot effectively prevent mutated cells from proliferating.

By drawing this conclusion, the researchers have not only identified a potential explanation for the early development of pediatric tumors, but have laid the groundwork for new cancer therapies. In short, since early tumor growth seems to be caused by cells' rapid bypass of the damage checkpoints instead of the gradual accumulation of damage at play in adult tumor growth, future treatments that can help cells increase ATM checkpoint activity or fight the overproduction of microRNAs may slow or stop the growth of cancerous pediatric tumors.

"These results help us to not only understand the early genesis of some tumors in children, but also why many solid tumors are highly sensitive to drugs and ionizing radiation that damage DNA," Houghton said. "They also help explain why, in children not cured by these treatments, resistance to therapy arises -- the rapid rate of mutation due to suppression of ATM. Potentially, the rate of mutations that lead to drug or radiation resistance could be slowed by targeting mTOR."