Young children have a high risk for developing severe, long-lasting impairments in
their brain, heart, and other vital organs from chemotherapy and
radiation treatments. In adults, however, these tissues are relatively
This disparity, which has never been explained, creates a
complicated balancing act for doctors - administering doses high enough
to have a chance of curing young cancer patients while minimizing the
risk of long-term cognitive and heart damage. This "therapeutic window"
is particularly narrow in infants and young children compared to adults,
whose vital organs are more resilient to intense treatment.
‘The tissues in the still-developing organs of young children are more prone to apoptosis, or programmed cell death, when subjected to toxic stresses like chemotherapy and radiation.’
Now, scientists at Dana-Farber Cancer Institute say they have discovered
a potential explanation for why brain and heart tissues in very young
children are more sensitive to collateral damage from cancer treatment
than older individuals. Reporting in Cancer Cell
, they show
that the tissues in these still-developing organs are more prone to
apoptosis, or programmed cell death, when subjected to toxic stresses
like chemotherapy and radiation.
"Apoptosis, in which molecular signals order cells to self-destruct,
plays an important role in deciding the "fate" of a developing cell -
that is, its final form and function in the body. For example, apoptosis
allows the "pruning" of brain cell connections that aren't needed or
productive in the fully formed brain. But active apoptosis in the early
brain "also sets the stage for extremely high sensitivity to any type of
damage or stress, especially that induced by radiation or
chemotherapy," said Kristopher A. Sarosiek, an assistant professor
of radiation biology at the Harvard T.H. Chan School of Public Health,
and first author of the paper. He was formerly a postdoctoral fellow in
the Dana-Farber laboratory of Anthony Letai, who is senior
author of the publication.
Cancer cells, however, often die through apoptosis when attacked by
chemotherapy, radiation, and other treatments, although cancer cells try
to escape the death orders by activating "pro-survival" signals to
countermand the death commands. Letai previously developed a test called
BH3 profiling that can measure inside any cell the relative dominance
of pro-survival or pro-death signals, which are mediated by a family of
Proteins called BAX and BAK are key "executioner" molecules
that signal cells to self-destruct. A cancer cell in which apoptotic
death signals are dominant, is said to be "highly primed" for
self-destruction and therefore easily killed by therapy, while a cell
with low priming is more resistant to death or damage.
In the new study, the researchers measured the priming of cells in
normal cells and tissues. They found that in most normal adult tissues,
including the brain and the heart, the machinery needed to perform
apoptosis is nearly completely absent. In contrast, this molecular
machinery is abundant in newborn and very young rodents. As a result,
brain and heart cells were therefore much more vulnerable to undergoing
cell death when exposed to chemotherapy or radiation.
After determining in mouse models that heart and brain cells grew
more resistant to treatment toxicity with age, the scientists tested the
hypothesis in human cells. They obtained fresh samples of tissue that
had been removed from brains of children and adults during surgery to
prevent intractable epileptic seizures. As in the mice, the youngest
human brain cells were more highly primed with apoptotic machinery and
vulnerable to chemotherapy and radiation damage.
Human brain and heart cells are most highly primed for apoptosis
until four to six years of age, said the researchers, making that period
prior to that the most risky for treatment-related damage. After that,
priming continues to be reduced, but tissues don't become firmly
resistant to damage until closer to adulthood, they said.
Because they identified the apoptosis molecules involved in tissue
damage, the study "has uncovered some opportunities to selectively block
apoptosis in our healthy tissues and prevent toxicity from radiation or
chemotherapy while still maintaining sensitivity within cancer cells,"
said Sarosiek. "We are actively pursuing the identification of new
medicines that can be used exactly for this purpose."