Balancing act between birth defects and cancer

Balancing act between birth defects and cancer

Researchers have made a surprise discovery about how subtle changes in the way cell survival is regulated during embryonic development can have drastic health implications.

The study, published in the journal Cell Reports, suggests that it is important to strike a healthy balance between too little cell death, which can cause cancer, and too much cell death, which can lead to developmental abnormalities.

Programmed cell death, also known as apoptosis, is a process that removes unwanted cells from the body. Apoptosis is crucial for normal development, for example removing the webbing between our fingers.

In this new study, researchers discovered that subtle changes in the regulation of apoptosis can have drastic consequences on development, particularly of the face and brain.

"There is a remarkably tight balance between the 'pro-survival' and 'pro-death' proteins that regulate cell death during development," the senior author said. "We found that reducing certain regulators by only 50 per cent, which is relatively subtle for these types of experiments, can cause craniofacial abnormalities such as eye and palate defects."

The senior author said altered levels of apoptotic regulators could be due to differences in the genes themselves, but could possibly also be affected by environmental factors such as nutritional deficiencies or infections.

"The 'clearing out' of damaged cells helps to safeguard tissues against cancer formation. This is important as cells that grow rapidly - such as those present during development - are intrinsically at risk of becoming cancerous.

"However, if the amount of pro-survival proteins dips too low during development, there may not be enough cells produced for structures such as the face and brain to form properly, resulting in devastating birth defects," another author said.

"Our discovery of the fine balance between apoptotic regulators during development was a complete surprise.

"We were actually studying the role of two pro-survival proteins, called MCL-1 and BCL-XL, in blood cancer, not embryonic development, so it was a total shock when we halved the amount of both proteins and saw dramatic developmental abnormalities," another author said.

Authors explored the rate-limiting roles of MCL-1 and BCL-XL in development and show that combined loss of single alleles of Mcl-1 and Bcl-x causes neonatal lethality. Mcl-1+/–;Bcl-x+/– mice display craniofacial anomalies, but additional loss of a single allele of pro-apoptotic Bim (Bcl2l11) restores normal development.
These findings demonstrate that the control of cell survival during embryogenesis is finely balanced and suggest that some human craniofacial defects, for which causes are currently unknown, may be due to subtle imbalances between pro-survival and pro-apoptotic BCL-2 family members.