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Mammals have developed elaborate
mechanisms to prevent disease and injury
and to initiate healing responses should
those prevention mechanisms fail. A good
example of a disease-prevention mecha-
nism is cellular senescence, a state in
which cell division is permanently arrested
(reviewed in Collado et al., 2007). This
phenomenon was originally discovered in
cultured primary cells that stop proliferat-
ing after a finite number of divisions (rep-
licative senescence). We now know that
replicative senescence is due, at least in
part, to erosion of telomeres, which occurs
at each cell division. Senescent cells
have a distinct phenotype that includes
characteristic alterations in morphology,
gene expression patterns, and chromatin
structure. Specific genes are known to be
required for senescence induction, thus
revealing the existence of a defined genetic
program. But why would cells develop a
mechanism to permanently halt prolifera-
tion? Findings in experimental mouse can-
cer models and with human tumor sam-
ples hinted at the answer: precancerous
tissues are composed of senescent cells
(reviewed in Campisi, 2005; Sharpless
and DePinho, 2005). These observations
led to the notion that induction of cellular
senescence provides an intrinsic barrier
to cancer development by preventing the
proliferation of cells that are damaged or
at risk for neoplastic transformation. In this
issue, Krizhanovsky et al. (2008) add a new
dimension to the cellular senescence story
by demonstrating that senescence is also
required in the normal response to injury
in the liver.
In their original studies of the physi-
ological response to liver damage in a
mouse model, Krizhanovsky and col-
leagues, rather surprisingly, observed
senescent cells in the liver. In their liver
injury model, mice are treated with the
chemical carbon tetrachloride to induce
fibrosis, the primary response of the
liver to injury. Fibrosis is a wound heal-
ing process characterized by the depo-
sition of extracellular matrix components
including collagens, proteoglycans, and
fibronectins, which help to encapsulate
the injury site (reviewed in Friedman,
2008). Liver fibrosis is a precursor to
cirrhosis, a significant health problem
caused by diverse liver-damaging agents
such as excessive alcohol, viral hepatitis,
and toxins. Hepatic stellate cells (HSCs)
are the primary modulators of liver fibro-
sis and are activated following damage
to hepatocytes, the predominant cell
type in liver tissue. Activated HSCs are
characterized by increased prolifera-
tion and motility and, most importantly,
by increased synthesis of extracellular
matrix components. Krizhanovsky et al.
senescence: not Just for Tumor suppression
Michael R. Green1,*
1Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts
Medical School, Worcester, MA 01605, USA
Cellular senescence provides an intrinsic barrier to tumor development by preventing the prolif-
eration of cells that are at risk for malignant transformation. In this issue, Krizhanovsky et al.
(2008) report that senescence is an important player not only in tumor suppression but also in the
response of liver tissue to injury.