Sci. Aging Knowl. Environ., 15 May 2002
Backup Plan: Senescence fights tumors when apoptosis fails (Cancer; Senescence)
Key Words: p53 p16 INK4a ARF cyclophosphamide
Abstract: Treating cancer often seems more like gambling than science. Some tumors yield to a particular chemotherapeutic agent, whereas others of the same type thrive in spite of the drug. Genetic differences among tumors are thought to underlie these divergent responses. Chemotherapy works in part by triggering cell suicide, and mutations that disrupt this process--called apoptosis--can confer drug resistance. Now, researchers present evidence that cellular senescence--a program that permanently arrests cell growth--also influences treatment outcome, a finding that might lead to better therapies. Furthermore, the discovery bolsters the possibility that senescence promotes aging.
"For many years, people believed that chemotherapy drugs damaged cells, which just blew up," says Scott Lowe, a cancer geneticist at Cold Spring Harbor Laboratory in New York and the study's senior author. But researchers now know that drugs disable cancer in part by triggering apoptosis, a normal process that eliminates potentially unruly cells. The compounds might also spur cellular senescence, but scientists have long questioned whether the process even occurs in animals, says Tyler Jacks, a cancer geneticist at the Massachusetts Institute of Technology in Cambridge. Although a few researchers have found evidence for senescence in live organisms and some have proposed that it fosters aging, the process's significance remains an open question (see "More Than a Sum of Our Cells").
To investigate the role of senescence in chemotherapy, Schmitt and colleagues bred mice that produce lymphomas with defined mutations in apoptosis and senescence genes. Although the tumors in these animals are pathologically identical, their response to cyclophosphamide (CTX) varies. "Some can be cured, and others just laugh at the drug and come back," says Lowe.
The researchers transplanted the tumors into mice and treated the animals with CTX. As expected, the compound requires apoptosis to deliver its blow. After drug treatment, mice that carried tumors with functional apoptosis machinery survived longer than did animals whose tumors couldn't trigger this cell death program. But senescence partially makes up for the loss of apoptosis. Tumors with genetic blocks to both apoptosis and senescence were even more deadly than tumors with defects in apoptosis alone. The results suggest that CTX quashes tumors by exploiting senescence as well as apoptosis.
This study is the first to demonstrate that senescence can influence drug treatment outcome in animals, says cancer geneticist Igor Roninson of the University of Illinois, Chicago. Jacks adds, "There's an important need to understand how cancer cells respond to therapy," and until now, scientists have focused on apoptosis. "This work highlights the idea that another process is involved," he says. If we can understand the processes chemotherapeutic agents employ to stifle cancer, we can make better drugs and use them in a way that will be more effective, says Lowe. Furthermore, the fact that senescence genes affect tumor growth in mice lends support to the idea that senescence functions in whole animals, not just cultured cells, he adds: "We hope [that] this [finding] stimulates more excitement about the senescence program as a whole and about questions of its role in aging."
C. A. Schmitt, J. S. Fridman, M. Yang, S. Lee, E. Baranov, R. M. Hoffman, S. W. Lowe, A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335-346 (2002). [Abstract] [Full Text]
I. B. Roninson, E. V. Broude, B.-D. Chang, If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. Drug Resist. Updates 4, 303-313 (2001). [Abstract] (Full text is not available online)
Citation: C. Aschwanden, Backup Plan: Senescence fights tumors when apoptosis fails (Cancer; Senescence). Science's SAGE KE (15 May 2002), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/19/nw60
Science of Aging Knowledge Environment. ISSN 1539-6150