However, a new study has found these cells also spew proteins into the cells’ surrounding environment. The process, called cellular senescence, causes inflammation and sets up conditions that support the development of age-related diseases including, ironically, cancer.
The findings, by Buck Institute scientists, mark the first comprehensive molecular description of a paradoxical process that prevents cancer in younger people, but promotes age-related cancers and other maladies later in life. The findings appear in the December 2, 2008 edition of the on-line, open access journal PLoS Biology.
“We provide for the first time a broad molecular description of how this well known mechanism for cancer prevention drives aging and age-related disease by changing the local tissue environment,” said Buck Faculty member Judith Campisi, PhD, lead author of the study who is also Senior Scientist at Lawrence Berkeley National Laboratory.
The study shows that the senescent cells secrete inflammatory, growth stimulating, immunomodulatory, and other proteins that dramatically change the tissue microenvironment, both in cell culture and in response to DNA-damaging chemotherapy in human patients. The human data compared tissue samples from prostate cancer patients that were obtained prior to and after completing chemotherapy.
The study also showed that normal cells that acquire a highly active mutant version of a cancer-promoting protein known as RAS secrete higher levels of the tissue-altering molecules, as do cells that lose functions of the tumor suppressor protein p53. The study explains why senescent cells promote the growth and aggressiveness of nearby precancerous or cancer cells, and further defines a new mechanism by which precancerous or cancer cells that have lost the p53 tumor suppressor, or gained an oncogene such as RAS, promote cancer so efficiently.
“This study defines a new paradigm for how oncogenes promote, and how tumor suppressor genes suppress the development of cancer,” said Campisi. “The established role for these genes is to control the cell itself. Our findings show that both types of genes also strongly change the tissue microenvironment, and therefore control cancer by mechanisms that depend not only on the response of the affected cells themselves, but also on the response of neighboring cells, or the local tissue environment.” Campisi said the findings also help explain why cancer patients feel so sick when they get chemotherapy. “Chemotherapy is brutal -- both normal and cancerous cells are forced into senescence, with resulting secretion of inflammatory factors that can produce flu-like symptoms during treatment,” Campisi said.
While Campisi emphasizes that chemotherapy can cure cancer, she says the study provides a cautionary note for younger patients who receive treatments that could promote the development of further cancers later in life. Campisi said the study points out the need for new biologically targeted therapies for cancer that exploit more specific differences between normal and cancer cells. Current DNA damaging chemotherapy focuses on cells that divide rapidly -- impacting cancer cells, as well as all dividing cells including cells in the alimentary canal and hair follicles.
The study has major implications for age research. Campisi adds, “This dynamic between cancer prevention and aging is exactly what is predicted by antagonistic pleiotropy, a major evolutionary theory of aging, which explains the trade-offs between early fitness and late life survival.” The results suggest that a cellular response that likely evolved to protect from early life cancer can promote late life pathology, including, ironically, late life cancer. The challenge now is to preserve the anti-cancer activity of the senescence response while dampening its pro-aging effects.
The next phase of the ongoing research involves efforts to encourage the body to eliminate senescent cells more rapidly than it normally does. “That’s got to be the goal,” said Campisi. “Although senescent cells exist for the good purpose of preventing cancer, we don’t want them to hang around – we want the body to be able to get rid of them.”
Other researchers involved in the study include Francis Rodier and Denise P. Muñoz of the Buck Institute, along with Jean-Philippe Coppé, Christopher K. Patil, and Joshua Goldstein (now at the Novartis Research Foundation) of the Life Sciences Division of Lawrence Berkeley National Laboratory, Berkeley CA; Pierre-Yves Desprez of the California Pacific Medical Center, San Francisco CA; and Yun Sun and Peter S. Nelson of the Fred Hutchinson Cancer Research Center, Seattle, WA. The work was supported by grants from the National Institutes of Health, the Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence, and the Larry L. Hillblom Foundation.
About the Buck Institute:
The Buck Institute is the only freestanding institute in the United States that is devoted solely to basic research on aging and age-associated disease. The Institute is an independent nonprofit organization dedicated to extending the healthspan, the healthy years of each individual’s life. The National Institute on Aging designated the Buck a “Nathan Shock Center of Excellence in the Biology of Aging,” one of just five centers in the country. Buck Institute scientists work in an innovative, interdisciplinary setting to understand the mechanisms of aging and to discover new ways of detecting, preventing and treating conditions such as Alzheimer’s and Parkinson’s disease, cancer, diabetes and stroke. Collaborative research at the Institute is supported by new developments in genomics, proteomics and bioinformatics technology. For more information: http://www.buckinstitute.org.
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