Cellular senescence, cancer and

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Lawrence Berkeley National Laboratory
September 10, 2005 SENS2, Cambridge
Cellular senescence, cancer and aging
Buck Institute for Age Research
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Suppressing cancer costs -- aging
Deplete proliferating/ stem cell pools
---gt Tissue atrophy/degeneration
Deplete proliferating/stem pools Cell dysfunction
---gt loss of tissue function/homeostasis
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Cellular Senescence Suppresses Cancer
Cancer cells acquire mutations that abrogate
the senescence response
Mutations that dampen cellular senescence
greatly increase susceptibility to cancer
Cellular senescence is controlled by two
powerful gatekeeper tumor suppressor pathways
(p53 and pRB)
Mouse model, human tumor data ----gt importance
of cell senescence for limiting cancer
progression
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The senescent phenotype Altered pattern of gene
expression
Cell cycle regulation
Cell structure
Metabolism
Biologically active secreted molecules Proteinases
Cytokines Growth factors
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Do senescent cells disrupt normal
and/or neoplastic tissue structure/function? (eff
ects of senescent stromal fibroblasts
on epithelial cells)
Jean-Philippe Coppe, Pierre Desprez, Ana
Krtolica, Simona Parrinello, Christopher Patil
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Senescent fibroblasts disrupt morphology and
function of mammary epithelial cells
BM PreS Fb BM Sen Fb
Pre-S Fb Sen Fb
b-casein
E-cadherin
b-casein DAPI
Parrinello et al., J Cell Sci, 2005
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Senescent fibroblasts disrupt ductal
morphogenesis of normal mammary epithelial cells
Presenescent fibroblasts
Number
Core Area
PRIMARY
SECONDARY
TERTIARY
Parrinello et al., J Cell Sci, 2005
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Senescent fibroblasts stimulate proliferation of
premalignant and malignant epithelial cells
Krtolica A et al., Proc Natl Acad Sci, 2001
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Senescent Fibroblasts Stimulate Tumorigenesis of
Premalignant Epithelial Cells In Vivo
100
SCp2 cells alone
0
200
Presenescent Fibroblasts
100
Tumor size (mm3 x 10)
0
200
Senescent Fibroblasts
100
0
Days
40
80
120
Krtolica A et al., Proc Natl Acad Sci, 2001
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Modeling effects of senescent cells in the
mouse Oxygen matters
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Senescent phenotype of mouse fibroblasts
Mouse cells undergo rapid replicative senescence
in culture, despite long telomeres telomerase
Mouse Fibroblasts (MEFs)
Human Fibroblasts
HaCAT
S1
SCp2
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Severe oxidative damage causes replicative
senescence of murine cells in culture
Parrinello et al., Nature Cell Biol, 2003
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How do senescent cells influence the behavior
of neighboring cells?
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The senescence-associated secretory phenotype is
conserved and complex
Jean-Philippe Coppe, Pierre Desprez, Ana
Krtolica, Simona Parrinello, Christopher Patil
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Conclusions from antibody arrays
Senescent stromal cells overexpress/secrete many
cytokines, proteases, growth factors (senescence
secretory phenotype)
There are many similarities among cells induced
to senesce by different stimuli
There are similarities in the secretory
phenotypes of senescent human and mouse stromal
cells, BUT oxygen matters
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Can the senescent phenotype be reversed without
reversing the senescent growth arrest?
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Senescent fibroblasts stimulate MEC ductal
hyperplasia through MMP-3
Parrinello et al., J Cell Sci, 2005
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THANKS! Jean-Philippe Coppe Ana
Krtolica Christopher Patil Simona Parrinello (U
College London) Christian Beausejour (McGill
U) Pierre Desprez -- CPMC Joe Gray, Rich Neve --
LBNL Kalin Kauser -- Berlex