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Lawrence Berkeley National Laboratory
September 10, 2005
SENS2, Cambridge
Cellular senescence, cancer and
aging
Buck Institute for Age Research
Suppressing cancer costs -- aging
Tumor Suppressor
mechanisms
Aging
Phenotypes
Late life
phenotypes,
including cancer
Caretakers
Gatekeepers
(prevent/ (eliminate/arrest
repair DNA
damaged,
damage,
mutant cells)
mutations)
(antagonistic
pleiotropy)
Apoptosis
Deplete proliferating/
stem cell pools --->
Tissue atrophy/degeneration
Senescence
Longevity
assurance
Deplete proliferating/stem pools
Cell dysfunction ---> loss of
tissue function/homeostasis
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 ----> importance of
cell senescence for limiting cancer progression
Cellular Senescence Induced by Many
(Cancer-Causing) Stimuli
Chromatin
Instability
DNA
Damage
Irreversible
arrest of
cell
proliferation
Supraphysiological
Mitogenic/
Stress Signals
Oncogenes
Short/dysfunctional
telomeres
(REPLICATIVE SENESCENCE)
CELLULAR SENECENCE:
Complex Senescent Phenotype
Irreversible
Growth
Arrest
Resistance
to
Apoptosis
Altered
Function/Gene
Expression
The senescent phenotype:
Altered pattern of gene expression
Cell cycle regulation
Cell structure
Metabolism
Biologically active secreted molecules
Proteinases
Cytokines
Growth factors
YOUNG TISSUE
YOUNG TISSUE
EPITHELIUM
"Initiated" Cell
Epithelial EPITHELIUM
Basement Membrane
Cells
Basement Membrane
STROMA
Fibroblasts
STROMA
AGING ?
AGING ?
Senescent
Epithelial Cell
Senescent
Epithelial Cell
OLD TISSUE
OLD TISSUE
EPITHELIUM
EPITHELIUM
Basement Membrane
Basement Membrane
STROMA
STROMA
Senescent Fibroblast
Degradative & inflammatory
molecules, growth factors, etc
INCIDENCE
Degradative enzymes,
Inflammatory cytokines, etc.
Neoplastic
Growth
Senescent Fibroblast
Mutations
Senescent cells
CANCER
AGE
Do senescent cells disrupt normal and/or
neoplastic tissue structure/function?
(effects of senescent stromal fibroblasts on
epithelial 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
Pre-S Fb Sen Fb
b-casein
E-cadherin
b-casein
DAPI
Parrinello et al., J Cell Sci, 2005
Senescent fibroblasts disrupt ductal morphogenesis
of normal mammary epithelial cells
Presenescent fibroblasts
Senescent fibroblasts
Primary duct
Secondary duct
Number
Core Area
Core
PRIMARY
SECONDARY
TERTIARY
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
Tumor size (mm3 x 10)
100
SCp2 cells alone
0
200
100
+ Presenescent
Fibroblasts
0
200
+ Senescent
Fibroblasts
100
0
40
Krtolica A et al., Proc Natl Acad Sci, 2001
80
120
Days
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
Epithelial Cell Growth
Presenescent
Senescent
Human Fibroblasts
HaCAT
SCp2
S1
Mouse Fibroblasts
(MEFs)
SCp2
HaCAT
S1
Severe oxidative damage causes
replicative 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/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
Can the senescent phenotype be
reversed without reversing
the senescent growth arrest?
Senescent fibroblasts stimulate MEC ductal
hyperplasia through MMP-3
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Parrinello et al., J Cell Sci, 2005
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