Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new...
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![Page 1: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/1.jpg)
Aging and Cancer: the Double-edged sword of cellular senescence
And
How to teach an old cell new tricks!
Lawrence Berkeley National Laboratory and Buck Institute for Age Research
![Page 2: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/2.jpg)
Cancer Rises Exponentially with Age
AGE
INC
IDE
NC
E
Age is largest single risk factorIncidence vs mortality
![Page 3: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/3.jpg)
What Causes Cancer?
Mutations, mutations, mutations …
AND
A permissive tissue
![Page 4: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/4.jpg)
Organisms with renewable tissueshad to evolve mechanisms
to prevent cancer
Tumor Suppressor Mechanisms
![Page 5: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/5.jpg)
Tumor Suppressor Mechanisms/Genes
(eliminates or arrests potential cancer cells)
Apoptosis (programmed cell death)Cellular senescence
CARETAKERS Prevent or repair genomic damage
(prevent mutations)
GATEKEEPERS Control cellular responses to damage
![Page 6: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/6.jpg)
Caretaker tumor suppressor genes arelongevity assurance genes
Gatekeeper tumor suppressor genes areantagonistically pleiotropic
![Page 7: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/7.jpg)
Antagonistic Pleiotropy
What’s good for you when you are young,can be bad for you when you are old.
![Page 8: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/8.jpg)
Aging before cell phones ……..
100%
SU
RV
IVO
RS
AGE
"Natural" Environment(hazards, predators, infection, etc.)
80 and >3-4
"Protected" Environment (climate control, biomedical intervention etc.)
40 yrsHUMANS:4 mos MICE:
![Page 9: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/9.jpg)
Aging before cell phones ……..
100%S
UR
VIV
OR
S
AGE
"Natural" Environment(hazards, predators, infection, etc.)
"Protected" Environment (climate control, biomedical intervention etc.)
Mutation Accumulation
Antagonistic Pleiotropy
![Page 10: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/10.jpg)
Cellular Senescence:A Gatekeeper Tumor Suppressor
Induced by potentially oncogenic stimuli
Most tumor cells acquire mutations that abrogate the senescence response
Controlled by p53 and pRB -- tumor suppressorsinactivated in most tumors
Mouse models/human cancer-prone syndromes
![Page 11: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/11.jpg)
Short/dysfunctionaltelomeres
(REPLICATIVE SENESCENCE)
DNADamage Oncogenes
ChromatinInstability
Stress/Signals
Cellular Senescence: Induced by Potentially Cancer-Causing Events
Irreversiblearrest of
cell proliferation
![Page 12: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/12.jpg)
The senescence response
is not simply an arrest of
cell growth
![Page 13: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/13.jpg)
The Senescent Phenotype
IrreversibleGrowth Arrest
Resistanceto
Apoptosis
AlteredDifferentiated
Functions
![Page 14: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/14.jpg)
Selected/Unselected (deleterious) Traits
IrreversibleGrowth Arrest
Resistanceto
Apoptosis
AlteredDifferentiated
Functions
Cellular Senescence and Antagonistic Pleiotropy
Unselected traits of little consequence, unless senescent cells accumulate to appreciable levels
![Page 15: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/15.jpg)
Senescent Cells Accumulate In Vivo
With Increasing AgeSkin
RetinaLiver
At Sites of Age-Related PathologyVenous ulcers
Atherosclerotic plaquesBenign prostatic hyperplasiaPreneoplastic hepatic lesions
![Page 16: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/16.jpg)
Senescent Cells May Contribute to Aging Phenotypes/Diseases …….
Including Cancer
![Page 17: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/17.jpg)
Ana KrtolicaSimona Parrinello
Steve Lockett - LBNL Imaging Group
Pierre Desprez - CPMC
Proc. Natl Acad. Sci USA 98:12072-12077 (2001)
![Page 18: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/18.jpg)
Ep
ith
elia
l F
luo
resc
ence
HaCAT SCp2 S1
Senescent Fibroblasts Stimulate the Proliferation of Premalignant Epithelial Cells
Premalignant Epithelial Cells
Fibroblasts:Presenescent
Senescent
![Page 19: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/19.jpg)
Ep
ith
elia
l F
luo
resc
ence
AdultNHEK
Neonatal NHEK
Adult HMEC
Senescent Fibroblasts Do NOT Stimulate Normal Epithelial Cells
Fibroblasts:Presenescent
Senescent
Genetically Normal Human Epithelial Cells
![Page 20: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/20.jpg)
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
![Page 21: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/21.jpg)
![Page 22: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/22.jpg)
Christian BeausejourAna Krtolica
Francesco Galimi (Verma lab, Salk Institute)Masasha Narita, Scott Lowe (CSH)
Paul Yaswen (LBNL)
EMBO J 22:4212-4222 (2003)
![Page 23: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/23.jpg)
Senescence Response, Controlled by p53 and pRB Pathways
p53 pRB
Growth Arrest + Senescent Gene Expression
Tx Changes(downstream effectors)
ARF
MDM2
CDK4
p16
![Page 24: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/24.jpg)
Lentiviruses for high-efficiency expression of genes in senescent cells
Lenti-GSE (inactivates p53)
Lenti-CDK4m (inactivates pRB)
Lenti-p16 (activates pRB)
Lenti-p16(RNAi) (inactivates pRB)
p53 pRB
ARF
MDM2
CDK4
p16
![Page 25: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/25.jpg)
SenescentBJ
(foreskin fb)
SenescentWI-38
(fetal lung fb)
+ Lenti-GSE (inactivate p53)
20 DoublingsNo proliferation
![Page 26: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/26.jpg)
0
20
40
60
80
100
0 20 40 60 80 1000
5
10
15
20
25
GSE
LgT
LgTK1
CDK4
GF
Ph
TE
RT
GS
E
Lg
T
Lg
TK
1
GS
E+
Lg
T
% L
N
S-BJ
% GROWTH: 0 0 >90 60 40 >90 20*
Po
pu
lati
on
do
ub
lin
g
Days post infection
S-BJ rescuedC
DK
4
0
20
40
60
80
100
GF
P
hT
ER
T
GS
EL
gT
Lg
TK
1G
SE
+L
gT
% L
N
S-WI
CD
K4
CD
K4
+G
SE
% GROWTH: 0 0 <1 <1 <1 <1 0 <1
GSE
LgT, LgT[K1]
CDK4m
![Page 27: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/27.jpg)
p53 inactivation can reverse the senescent growth arrest of BJ, but not WI-38, cells
What distinguishes reversiblyfrom irreversibly senescent
cells??
![Page 28: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/28.jpg)
Fibroblasts differ in expressionof p16 at senescence:
BJ = low p16WI38 = high p16
BJ WI38 P S P S
actin
p16
pRBCDK4
p16
![Page 29: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/29.jpg)
Do differences in p16 expression
explain differences in
reversibility of the senescence arrest?
![Page 30: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/30.jpg)
Presenescent BJ fibroblasts (low p16):
DNA synthesis, but no proliferation
0
40
80
100
% g
row
th
GFP p16 p16+
GSE
p16+
LgT
LgT +GFP
LgT +p16
1) + lenti-p16
2) + lenti-GSE
![Page 31: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/31.jpg)
Presenescent WI-38 fibroblasts (high p16):
DNA synthesis + proliferation
0
40
80
100%
gro
wth
GFP p16RNAi + Sn
p16RNAi
+Sn +
GSE
Sn +GFP +LgT
Sn +p16RNA +LgT
p16RNAi
+Sn+
LgT
1) + lenti-p16-RNAi ----> Senescence
2) + lenti-GSE
![Page 32: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/32.jpg)
p53 maintains the senescent state; p16 maintains a dominant barrier to reversal
The senescent phenotype is reversibleupon p53 inactivation ……
Providing the p16/pRB pathway hasnot been engaged
Why does p16 render the senescencegrowth arrest irreversible?
![Page 33: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/33.jpg)
HYPOTHESIS: p16 enables pRB toestablish an “irreversibly” repressive
chromatin state that, once established,is independent of p16 or pRB
Senescent cells form RB-dependent heterochromaticdomains that repress positive acting cell cycle genes
Lowe and colleagues, Cell, 2003
Once cells express high levels of p16, they nolonger require p16 or active pRB to maintain the
senescence growth arrest
![Page 34: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/34.jpg)
p16 renders senescence irreversible
0
40
80
100
% g
row
thGFPp16 p16
+GSE
p16+
LgT
LgT +GFP
LgT +p16
PBJ +p16
0
40
80
100
% g
row
th
GFPp16RNAi + Sn
p16RNAi
+Sn +
GSE
Sn +GFP +LgT
Sn +p16RNAi +LgT
p16RNAi
+Sn+
LgT
PWI +P16-RNAi
![Page 35: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/35.jpg)
Senescence is not necessarily irreversiblein human cells
Hint: ask about mouse cells!
p53 inactivation is not a recommended therapy(but p53 modifiers, such as SIR2, may be!)
What determines the extent to which cells express p16?
How can we reverse thep16/pRB-initiated chromatin?
![Page 36: Aging and Cancer: the Double-edged sword of cellular senescence And How to teach an old cell new tricks! Lawrence Berkeley National Laboratory and Buck.](https://reader030.fdocuments.in/reader030/viewer/2022032517/56649c895503460f9494198e/html5/thumbnails/36.jpg)
Aging and Tumor Suppression
Tumor suppressors
Aging Phenotypes Cancer
Can tumor suppression and agingbe uncoupled??