Scientists at Israel’s Weizmann Institute of Science have discovered a biological mechanism that may provide a better knowledge of tissue regeneration and may also provide hints as to why some tumours recur after therapy.
Published in Nature Communications, the research uncovered a population of cells that kick-start programd cell death, but survive to assist restore badly injured tissue.
In trials with fruit fly larvae, the cells, called DARE cells, rapidly reproduced, replacing almost half of the injured tissue within 48 hours.
The finding provides insight into compensatory proliferation, a biological process wherein surviving cells grow to replace those lost by injury.
But the same survival mechanism might also be enabling cancer cells to survive treatment.
Apoptosis, or programd cell death, allows the body to destroy damaged, ageing and undesirable cells. Caspases are a family of enzymes that start and do the process.
Research by Prof. Eli Arama of the Molecular Genetics Department at the Weizmann Institute shows that caspases can also undertake roles beyond cell killing.
His researchers felt they might have a role in regenerating tissue.
Led by Dr Tslil Braun, the researchers reproduced a classic 1970s experiment in which radiation-damaged fly larvae grew functional wings. Using contemporary genetic methods, they followed cells that initiated the early phases of apoptosis yet survived.
‘We wanted to find cells that pressed the self-destruct button but nevertheless live on,’ Braun said.
Researchers found DARE cells that not only survived radiation but multiplied and repaired nearly half of the damaged tissue in 48 hours.
They also identified a second group, called NARE cells. NARE cells survived, however, unlike DARE cells, did not activate their initiator caspase and contribute to regeneration.
That distinction was critical. This compensatory growth was abolished if DARE cells were eliminated. The researchers also detected signals from dying cells that activated DARE cells, driving rapid tissue repair.
The results showed that DARE cells initiate apoptosis normally. But the process is halted before the effector caspases can carry out cell death.
They traced the stoppage to a molecular motor protein that seems to bind the initiator caspase to the cell membrane, inhibiting the activation of enzymes needed to finish off the death of the cell.
When the team shut off the motor protein, DARE cells perished and tissue repair was hampered.
Arama observed that hyperactivation of this same protein had previously been linked to the formation of cancerous tumours, suggesting that cancer cells might be using a similar technique to resist apoptosis.
While the finding doesn’t prove this process causes cancer to return in people, it presents a path for additional research.
Then the scientists looked at if the DARE cells could carry their resistance to death on to their offspring. They then irradiated the tissue a second time and discovered that the number of cell deaths in the first few hours was half of that after the first irradiation. Most of the dead cells were of the NARE population. The cells descended from DARE cells were reported to be seven times more resistant to cell death than the cells of the original tissue .
“We wanted to know if death resistance is inherited by the descendants of death-resistant cells that survived the initial irradiation,\” Arama added.
The finding may help explain how cells that survive an injury develop traits that make them resistant to a later injury. However, such resistance in cancer may allow tumour cells to survive treatment and contribute to recurrence.
The researchers said their experiments were on fruit flies, and it is not yet clear if the results would be relevant to human tumours.
The study also found a feedback mechanism that appears to prevent over regeneration.
DARE cells give forth growth signals which cause NARE cells adjacent to divide. In exchange, NARE cells send signals that suppress DARE cell development. This creates a negative feedback loop that allows for tissue healing, but also helps avoid uncontrolled proliferation.
Understanding these systems could one day aid efforts to expedite healthy tissue regeneration and improve cancer treatment options, Arama adds.
“Many cancers begin in epithelial cells that have lost normal growth control, and many conventional cancer treatments aim to induce apoptosis, or self-destruction, in them,” he said.
“Our findings open the door to understanding why such treatments sometimes fail, and how they could be improved.”
“The finding gives us a new way to look at how the body responds to injury. A system that helps healthy tissue regenerate could be a means of survival for hazardous cells in other circumstances.
Now the problem for researchers is to work out how to reap the benefits of regeneration without giving cancer cells a route to escape treatment.
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