August 5, 2005
Could Suspended Animation Combat Cancer?
'Cellular senescence' might be used to put tumors to sleep, research suggests
A new strategy for fighting -- and perhaps preventing -- cancer has emerged from research on the genetics of malignant cells.The concept: Don't kill those cells, as is now done, but put them into a biological form of suspended animation called cellular senescence.
Four research groups, in the United States and abroad, are reporting studies in the Aug. 4 issue of Nature showing that this approach is a realistic new frontier in the war against cancer.
"What these four groups have done is to work with different model systems and different cancer types -- melanoma, lymphoma, prostate cancer -- in human and mouse systems, with different genetic lesions, all giving the same answer," said Dr. Ronald A. DePinho, who wrote an accompanying editorial in the journal.
Cellular senescence "occurs in the face of significant stress, such as DNA damage or oncogenic [cancerous] signaling," said DePinho, who is director of the Center for Applied Cancer Research at the Dana-Farber Cancer Center in Boston. "It is cellular stasis, suspended animation, in which the cells are still alive but have an inability to divide."
Laboratory studies using cell cultures have shown that senescence occurs, but there have been doubts about whether it happens in living animals, DePinho said.
"These studies have shown that in different tumor types with different genetic lesions, in the early phases of these cancers there is activation of a senescence response," he said. "It is not simply an artifact, but a real biological response that cells have to restrain cancer-promoting changes. Cellular senescence now joins the pantheon of biological responses to cancer."
An example of how this discovery might be put to medical use comes from one of the studies, in which researchers at Memorial Sloan-Kettering Cancer Center in New York City looked at the genetics of prostate cancer.
The study, led by Zhenbang Chen, an oncologist in the laboratory of Dr. Paolo Pandolfi, looked not at the specific genes that have been associated with prostate cancer but at two genes that work to suppress cancerous changes, PTEN and p53.
"These are both mutated frequently in prostate cancer," said Dr. David Shaffer, one of the Sloan-Kettering researchers. "We engineered mice to produce these mutations."
They found an unusual interaction. Inactivation of P53, which happens in a large percentage of human prostate cancer cases, led to massive cancer growth. But that growth did not occur if PTEN remained active. "If PTEN was active, that triggered the cells to go into senescence," Shaffer said.
The genetic work could lead to prostate cancer treatment and even prevention, Shaffer said. "We could prevent the tumors from growing if we kept p53 active," he said. "And if we could prevent the p53 pathway from being inactivated, we could cause cells that have this early mutation to go to sleep."
It is a long way from this basic research to medical use, Shaffer acknowledged. "But this going to open a lot of people's eyes," he said. "People at drug companies, oncologists will be asking whether it is a feasible approach to put cancer cells into permanent sleep. This is a whole new area of trying to prevent tumor cell growth."
Some very basic work must still be done, DePinho said. "At this point, we don't have a clear view of the molecular pathways that connect the oncogenic signaling to the senescence response," he said. "If we could understand that wiring, it would provide a method of attack."
A layman's guide to cellular senescence is provided by the American Federation for Aging Research.