Cellular senescence, cancer and aging
Buck Institute for Age Research
Lawrence Berkeley National Laboratory
September 10, 2005SENS2, Cambridge
Suppressing cancer costs -- aging
Tumor Suppressor mechanisms
AgingPhenotypes
Care-takers(prevent/
repair DNAdamage,
mutations)
Gate-keepers
(eliminate/arrestdamaged,
mutant cells)
Apoptosis
Senescence
Deplete proliferating/stem cell pools --->
Tissue atrophy/degeneration
Deplete proliferating/stem poolsCell dysfunction ---> loss oftissue function/homeostasis
Late lifephenotypes,
including cancer(antagonisticpleiotropy)
Longevityassurance
Cellular Senescence Suppresses Cancer
• Cancer cells acquire mutations that abrogate thesenescence response
• Mutations that dampen cellular senescence greatlyincrease susceptibility to cancer
• Cellular senescence is controlled by two powerfulgatekeeper tumor suppressor pathways (p53 and pRB)
• Mouse model, human tumor data ----> importance of cell senescence for limiting cancer progression
Short/dysfunctionaltelomeres
(REPLICATIVE SENESCENCE)
DNADamage Oncogenes
ChromatinInstability
SupraphysiologicalMitogenic/
Stress Signals
Cellular Senescence Induced by Many(Cancer-Causing) Stimuli
Irreversiblearrest of
cell proliferation
CELLULAR SENECENCE:Complex Senescent Phenotype
IrreversibleGrowth Arrest
Resistanceto
Apoptosis
AlteredFunction/Gene
Expression
The senescent phenotype: Altered pattern of gene expression
Cell cycle regulation
Cell structure
Metabolism
Biologically active secreted moleculesProteinasesCytokines
Growth factors
EPITHELIUMBasement Membrane
STROMA
Senescent Epithelial Cell
Senescent Fibroblast
EPITHELIUMBasement Membrane
STROMA
YOUNG TISSUE
OLD TISSUE
Degradative enzymes, Inflammatory cytokines, etc.
AGING ?
EpithelialCells
Fibroblasts
EPITHELIUMBasement Membrane
STROMA
Senescent Epithelial Cell
Senescent Fibroblast
OLD TISSUE
Degradative & inflammatory molecules, growth factors, etc
AGING ?
EPITHELIUMBasement Membrane
STROMA
YOUNG TISSUE "Initiated" Cell
Neoplastic Growth
AGEINC
IDE
NC
E
MutationsSenescent cells
CANCER
Do senescent cells disrupt normal and/orneoplastic tissue structure/function?
(effects of senescent stromal fibroblasts onepithelial cells)
Jean-Philippe Coppe, Pierre Desprez, Ana Krtolica, Simona Parrinello, Christopher Patil
Senescent fibroblasts disrupt morphology and function of mammary epithelial cells
BM + PreS Fb BM + Sen Fb
-casein DAPI
Pre-S Fb Sen Fb
-casein
E-cadherin
Parrinello et al., J Cell Sci, 2005
Presenescent fibroblastsPrimary duct
Secondary duct
Senescent fibroblasts
Core
Co
re A
rea
Nu
mb
er
PRIMARY SECONDARY TERTIARY
Senescent fibroblasts disrupt ductal morphogenesisof normal mammary epithelial cells
Parrinello et al., J Cell Sci, 2005
Senescent fibroblasts stimulate proliferation of premalignant and malignant epithelial cells
Krtolica A et al., Proc Natl Acad Sci, 2001
Senescent Fibroblasts Stimulate Tumorigenesis of Premalignant Epithelial Cells In Vivo
Days40 80 120
Tu
mo
r si
ze (
mm
3 x
10)
100
0
100
0
200
100
0
200
SCp2 cells alone
+ Presenescent Fibroblasts
+ Senescent Fibroblasts
Krtolica A et al., Proc Natl Acad Sci, 2001
Modeling effects of senescent
cells in the mouse:
Oxygen matters
Senescent phenotype of mouse fibroblasts
Mouse cells undergo rapid replicative senescence in culture, despite long telomeres + telomerase
PresenescentSenescent
SCp2 HaCAT S1
Ep
ith
elia
l Ce
ll G
row
th
HaCAT SCp2 S1
Human Fibroblasts Mouse Fibroblasts(MEFs)
Severe oxidative damage causesreplicative senescence of murine cells in culture
Parrinello et al., Nature Cell Biol, 2003
How do senescent cells influence the behavior of
neighboring cells?
The senescence-associated secretory phenotype is conserved and complex
Jean-Philippe Coppe, Pierre Desprez, Ana Krtolica, Simona Parrinello, Christopher Patil
Conclusions from antibody arrays
Senescent stromal cells overexpress/secretemany cytokines, proteases, growth factors
(senescence secretory phenotype)
There are similarities in the secretory phenotypesof senescent human and mouse stromal cells,
BUT oxygen matters
There are many similarities among cellsinduced to senesce by different stimuli
Can the senescent phenotype be reversed without reversing
the senescent growth arrest?
QuickTime™ and aTIFF (LZW) decompressor
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QuickTime™ and aTIFF (LZW) decompressor
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QuickTime™ and aTIFF (LZW) decompressor
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Parrinello et al., J Cell Sci, 2005
Senescent fibroblasts stimulate MEC ductal hyperplasia through MMP-3
THANKS!
Jean-Philippe CoppeAna Krtolica
Christopher Patil
Simona Parrinello (U College London)Christian Beausejour (McGill U)
Pierre Desprez -- CPMCJoe Gray, Rich Neve -- LBNL
Kalin Kauser -- Berlex