Current issue

Defying death
A dying cell's legacy may be to stimulate new growth
Hermann Steller is fascinated by death. Death of cells, that is. He has dedicated his research to understanding cell suicide, has dubbed proteins that he has discovered Grim and Reaper, and speaks passionately about “undead” cells that should die, but fail to follow through with their own demise.
Now the Rockefeller cancer biologist has found that from the dying can come new life — not a transmigration of cellular souls, but a mechanism of cell generation that is completely novel and has important implications for cancer research and treatment.
In the October issue of Developmental Cell, Steller, Hyung Don Ryoo, a postdoctoral fellow in his lab, and senior technician Travis Gorenc report that as cells commit suicide in response to stress or injury, such as DNA damage, they emit signals that result in the growth of new cells.
In other words, cell death may not be as straightforward a matter — of weeding out the weak and ill — as scientists thought. Rather, Steller and his lab colleagues demonstrated that in their fruit fly model of cell death, a damaged cell’s reaction to stress or injury is to trigger new growth nearby, ostensibly — and sensibly — to replace the dead cell.
Human cells seem to undergo the same process.
“What we show is that the dying cells themselves make a signal, a mitogen that can induce division and proliferation in other cells,” says Steller, who is head of Rockefeller’s Strang Laboratory for Apoptosis and Cancer Biology and a Howard Hughes Medical Institute investigator. “Anthropomorphically speaking, the cell is saying to its neighbors that ‘I am injured, I am going to die soon, and you have to do something to replace me.’”
While it has been known that in injured tissues cells can fill the gap created by those that have died, a process known as compensatory proliferation, “it has always been thought to be passive, that what was detected is the absence of cells which needed to be filled in,” he says. “What we have found is very different. We showed that it is the dying cells themselves that make a signal that pushes cells nearby to grow.”
Steller and Ryoo built upon their previous research showing how a fruit fly protein called Reaper triggers programmed cell death, or apoptosis. Reaper instructs the principal protein guarding against cell suicide to self-destruct. Once this protein, known as Drosophila IAP1, or DIAP1, is gone, proteins known as caspases are freed up; they are the key executioners of a cell.
Steller and his team knew that Reaper could remove DIAP1 in more than one way. So they next investigated whether it was important to apoptosis that DIAP1 destroyed itself. Ryoo looked at the biological role of this protein’s degradation by using a mutant DIAP1 in Drosophila larvae that could no longer self-destruct as it should have. The researchers found that cells with the mutant protein die. So Ryoo kept the cells alive by using proteins that inhibit caspases from destroying the cell.
“The idea was to prevent the death of cells that do not have DIAP1 and keep them alive — keep them undead — and see what happens,” says Steller. “But when we did this, tissue became several times its original size. This was a big surprise, because if you are saving cells that should normally die, the tissue should not be smaller, but it should certainly not be bigger.” Repeated experiments found the same phenomenon, including tumor-like outgrowths.
Ryoo discovered that the unexpected growth occurred in the area next to the undead cells. Upon further exploration, he discovered that the undead cells actually produced signals that stimulate cell division, triggering the growth. These signals, controlled by genes such as wingless (wg) and decapentaplegic (dpp), were already known to be involved in cell proliferation. The scientists also showed that dying cells activate a cell signaling pathway known as the Jun-N-terminal Kinase (JNK) pathway, which is needed to induce wg signaling.
“This is a very unexpected finding, even to us,” says Steller, who calls these findings one of his best research stories in a decade. “When some of the first findings emerged, I was very excited, but also very careful because it was such a radically new concept. It was not received with universal enthusiasm.”
If replicated in human cells, the findings could be revolutionary to cancer therapy. Cancer cells by definition are immortal — the mechanisms that lead to cell death have been turned off. Steller’s results suggest that toxic treatments such as radiation and chemotherapy that stress cancer cells may actually stimulate some cancer growth. Specifically, the signals produced by these undead cells may trigger the relatively few omnipotent cancer stem cells found within tumors to create more cancer cells.
“If cells that are stressed through treatment are somewhat resistant to apoptosis, and so are not rapidly cleared, they could continuously send out signals that result in a significant overgrowth of cells,” says Steller. While such a theory has yet to be proven in cancer cells, in the least, the findings suggest that therapies that engage the apoptosis pathway more directly than blunter treatments may avoid this crucial stress response, he says.
The discovery also has implications for beneficial cell regeneration. “Sometimes you want to have cells growing back if there is an injury, so there may be a way to boost this response,” says Steller. He is now looking at cells taken from the liver, an organ that can, to a limited degree, regenerate itself in response to viral infection or toxic stress, to see if they use this stress response pathway in a helpful manner.
“This is the start of something that needs further investigation, but it is a very testable model,” says Steller. “If anything, our notion of compensatory proliferation is sure to stimulate a lot of debate.”

November 19, 2004



2005   2004    2003    2001-2002    1999-2000

Home | About The Rockefeller University | Research and Faculty | Graduate School | Other Academic Programs | The Rockefeller University Hospital | Resource Centers | News and Publications | Events | The Rockefeller University Press | The Rockefeller Archive Center | Corporate Offices and the Board of Trustees | University Departments and Services| Comments