New studies probe mechanisms of death-defying anastasis
Ho Lam Tang
SAN FRANCISCO — Mostly dead is still partly alive, even for cells on the brink of suicide, new research suggests.
Near-death experiences may play a role in embryo development and help cancer cells that survive chemotherapy spread throughout the body, Denise Montell, a cell biologist at the University of California, Santa Barbara, reported December 6 at the annual meeting of the American Society for Cell Biology.
Montell described a recently discovered process called anastasis that saves cells in the midst of committing a type of cellular suicide known as apoptosis. She and others are only beginning to unravel how the process works. Preliminary results indicate that cells simultaneously kill themselves and hold on to a lifeline in case conditions improve, she said.
Scientists had thought that once a cell going through apoptosis activated an executioner molecule known as a caspase, the cell would surely die, said Claire Walczak, a cell biologist at Indiana University in Bloomington. But cells sometimes call off their attempted suicides at the last moment, even after the executioner starts working, cell biologist Ho Lam Tang discovered in 2008 while a graduate student at the Chinese University of Hong Kong. Tang, now at Johns Hopkins University, named the process anastasis, which in Greek means “rising to life.”
Tang’s discovery that apoptosis is reversible “was really shocking,” said Walczak. “It’s a really nice illustration of how adaptable cells are.”
Tang initially made the discovery by treating an immortal type of cancer cells, called HeLa cells, with a drug that stimulates apoptosis. Once the cells were dying, Tang washed away the drug and some of the cells recovered.
“That experiment is essentially what we do to patients” undergoing chemotherapy treatment, said J. Marie Hardwick, a cell and molecular biologist at Johns Hopkins. She reported with Tang last year in Scientific Reports that fruit fly egg cells can come back from apoptosis and even produce an adult fly.
Cancer patients are given a dose of chemotherapy drugs or radiation that causes cells to commit apoptosis. Then the treatments are stopped for a short time to allow the patient to recover. If cancer cells can come back through anastasis, they may cause a resurgence of the disease, Hardwick suggests. Many of the cells brought back by anastasis have genetic defects. “If you’ve already attempted to die, you’ve got problems,” Hardwick says.
Some cells that survive apoptosis brought on by stresses such as heat or irradiation can go on to divide and “do basically anything a normal cell can do,” Montell said. But unpublished work from her lab indicates that cells brought back to life by anastasis may never go back to their untreated state and may carry permanent memories of their near-death experiences, she said at the cell biology meeting.
Montell and colleagues compared gene activity in untreated cells and ones taken to the brink of death and allowed to recover for varying amounts of time. Cell survival genes are already being made while the cell is preparing to kill itself, her team discovered.
“Dying cells are actually hedging their bets. They’re on the brink of death. They don’t know if things are going to get better or get worse,” Montell said. After recovery, the reanimated cells begin to move and to stimulate blood vessel production. Those are things cells do when healing a wound, but they are also actions taken by tumor cells.
“This would be an extremely unbeneficial response if the cells in question happen to be cancer cells,” Montell said. The findings suggest that stopping anastasis may lead to more effective cancer treatments.
In some other cases, stimulating anastasis may benefit patients, Montell said, such as by saving heart cells after a heart attack or brain cells after a stroke. Those cells don’t divide much so there’s less risk of cancer and recovered cells could restore heart and brain function.
Scientists don’t know exactly how anastasis works — few researchers are even aware it happens — so it may take some time before anyone is able to start or stop anastasis at will, Hardwick said.
G. Sun et al. Anastasis, recovery from the brink of apoptotic cell death, in normal development and disease. American Society for Cell Biology annual meeting, San Francisco, December 6, 2016.
A. X. Ding et al. CasExpress reveals widespread and diverse patterns of cell survival of caspase-3 activation during development in vivo. eLife. Vol. 5, April 8, 2016, p. e10936. doi: 10.7554/eLife.10936.
H. L. Tang et al. In vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Scientific Reports. Vol. 5, March 11, 2015. doi: 10.1038/srep09015.
H. L. Tang et al. Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Molecular Biology of the Cell. Vol. 23, June 15, 2012, p. 2240. doi: 10.1091/mbc.E11-11-0926.
H. L. Tang et al. Reversibility of apoptosis in cancer cells. British Journal of Cancer. Vol. 100, December 16, 2008, p. 118. doi:10.1038/sj.bjc.6604802.
T. H. Saey. Disabling cellular assassin prevents cancer. Science News. Vol. 178, August 28, 2010, p. 8.