Cellular senescence, cancer and aging
Judith Campisi
Lawrence Berkeley National Laboratory, Berkeley CA 94720, USA and Buck Institute for Age Research, Novato, CA 94945, USA
Normal cells respond to DNA damage, dysfunctional telomeres and other
potentially oncogenic events by entering an essentially irreversible
state of arrested growth and altered function termed senescence. The
senescence response, like the apoptotic response, is an important tumor
suppressive mechanism for mammals. In addition, there is increasing
evidence that the senescence response may be an example of evolutionary
antagonistic pleiotropy and contribute to aging. That is, while this
response curtails the development of cancer early in life, the
accumulation of dysfunctional senescent cells later in life may cause
or promote aging phenotypes and the development certain age-related
pathologies, including, ironically, late life cancers. How might
senescent cells fuel aging and/or age-related disease? In addition to
the irreversible growth arrest, the senescence response is accompanied
by many changes in gene expression. Of particular importance,
senescent cells secrete a variety of molecules that can alter tissue
structure and function, thereby relaxing the ability of the tissue to
maintain normal cellular behavior. High-throughput analysis of the
secretory phenotype of senescent human and mouse fibroblasts reveals
that senescent cell secrete a large number of factors, including matrix
remodeling enzymes, epithelial growth factors, inflammatory cytokines,
and cytokines that stimulate cell migration and invasion. We find that
factors secreted by senescent fibroblasts can stimulate the
proliferation of epithelial cells with potentially oncogenic
mutations. Moreover, they can also compromise the ability of
neighboring normal cells to maintain optimal differentiated tissue
structures and functions. Thus, the accumulation of senescent cells
may link the decline in tissue function that is a hallmark of aging
with the rise in age-related cancer. Can the secretory phenotype of
senescent cells be blunted or reversed? We have had limited success in
this endeavor. Our recent ability to completely reverse the effects of
senescent stromal cells on ductal hyperplasia in a cell culture model
of mammary gland morphogenesis support concept that eliminating or
reducing the activities of senescent cells may retard age-related
decrements in tissue structure and function.
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