Aging and Cancer:
Rival Demons?
Aging
Cancer
Aging and Cancer are Biological Linked
Understanding Aging is
Key to Understanding Cancer
Cancer is linked to aging
What is cancer?
What causes cancer?
What limits cancer?
How are cancer and aging linked?
INCIDENCE
Cancer Rises Exponentially with Age
AGE
Age is the largest single risk factor
Incidence vs mortality
Similar to other age-related diseases
Cancer Incidence Scales with Life Span
100%
0
Humans
% ALIVE
CANCER INCIDENCE
Mice
100
1.5
3
60
120
AGE
Mice and Humans are ~ 97% Genetically Similar
Postponed Aging Delays Cancer
Mice
"Restricted"
Diet
100%
0%
CANCER INCIDENCE
% ALIVE
"Normal"
Diet
1
2
3
AGE
4
The RATE at which cancer increases
is proportional to the RATE of aging
Cancer is linked to aging
What is cancer?
What causes cancer?
What limits cancer?
How are cancer and aging linked?
Cancer is an abnormal mass (tumor),
resulting from cell proliferation,
that has the potential to kill the organism
Cancer is much more than cell proliferation
CANCER ARISES FROM
RENEWABLE TISSUES
Composition of Complex Organisms
CELLS
POSTMITOTIC
EXTRACELLULAR
MATERIAL
MITOTIC
(renewable)
(non-renewable)
Degenerative
disease
Degenerative disease
Cancer
Five Characteristics of Malignant Cells
Loss of growth control, including avoidance of
senescence (neoplasia)*
Avoidance of cell death (apoptosis resistance) *
Stimulation of blood vessle formation (angiogenesis)
Invasion into surrrounding tissue (invasion)
Ability to colonize distal tissues (metastasis)
Loss of growth control
(neoplasia)
Inappropriate cell division
Unlimited cell division potential
(cellular senescence; replicative immortality)
Activation of growth promoting genes
[oncogenes]
Inactivation of growth inhibitory genes
[tumor suppressor genes]
Avoidance of Apoptosis
(cell death)
Resistance to physiological
"death" signals
Resistance to damage-induced
death signals
(survival of cells with genomic instability)
Activation of growth promoting genes
[oncogenes]
Inactivation of growth inhibitory genes
[tumor suppressor genes]
Cancer is linked to aging
What is cancer?
What causes cancer?
What limits cancer?
How are cancer and aging linked?
Cancer cells acquire
malignant properties through
de novo somatic mutations
(activation of oncogenes or
inactivation of tumor suppressor genes)
Cancer cells also require
a tissue microenvironment that
permits the growth and survival of
mutant cells
(disruption of normal tissue
structure and function)
Mutations accumulate throughout life
Potentially oncogenic mutations are present
even in young apparently normal tissues
Tissue structure changes throughout life
Young tissues are often structurally distinguishable
from middle-aged and old tissues
If mutations and tissue structure change
throughout life, why then do we not get
cancer more often?
Cancer is linked to aging
What is cancer?
What causes cancer?
What limits cancer?
How are cancer and aging linked?
Years
Days/wks
Min/hrs
LIFE SPAN
Evolution of Long-Lived, Complex Organisms
Single-celled
No
Cancer
Multi-cellular,
Post-mitotic
Cancer
Multi-cellular, Post-mitotic +
Renewable tissues
ORGANISMS
CELL DIVISION IS RISKY!!
Risky business of CELL DIVISION
3 billion bp DNA:
Unpackaged
(loss of protection)
Replicated
(fidelity; repair)
Mutation Fixation
Organisms with renewable tissues
had to evolve mechanisms
to prevent cancer
Tumor Suppressor Genes
Two Classes of Tumor Suppressor Genes
• CARETAKERS -- act on the genome
Damage prevention and repair
• GATEKEEPERS -- act on cells
Apoptosis - eliminates potential cancer cells
Cellular senescence - prevents their growth
Apoptosis Suppresses Cancer
• Cancer cells frequently acquire mutations that
inhibit cells from sensing or processing
physiological death signals
• Mutations that dampen the apoptotic response
greatly increases susceptibility to cancer
• Apoptosis is controlled by the two most
powerful tumor suppresssor pathways
(p53 and pRB)
Cellular Senescence Suppresses Cancer
• Cancer cells frequently acquire mutations that
abrogate the senescence response
• Mutations that dampen the senescence response
greatly increases susceptibility to cancer
• Cellular senescence is controlled by the two
most powerful tumor suppresssor pathways
(p53 and pRB)
Caretaker tumor suppressor genes are
longevity assurance genes
Gatekeeper tumor suppressor genes can be
antagonistically pleiotropic
Aging before cell phones ……..
"Protected"
Environment
(climate control,
biomedical intervention
etc)
SURVIVORS
100%
”Hazardous"
Environment
(climate, predators,
infection, etc)
AGE
SURVIVORS
100%
"Natural"
Environment
(hazards, predators,
infection, etc.)
"Protected"
Environment
(climate control,
biomedical intervention
etc.)
AGE
Mutation Accumulation ("bad" genes can persist)
Antagonistic Pleiotropy
(what’s good for you when you’re young can be
bad for you when you’re old)
Why might gatekeeper tumor suppressors -be antagonistically pleiotropic??
APOPTOSIS -- culls defective cells…..
but deplete tissues of cells
CELLULAR SENESCENCE -- arrests
proliferation of defective cells …..
but senescent cells are dysfunctional
Testing the hypothesis that gatekeeper
tumor suppressors are
antagonistically pleiotropic:
Cellular senescence
Cellular Senescence: Arrests Cell Proliferation
In response to Potential Cancer-Causing Events
Chromatin
Instability
DNA
Damage
Irreversible
arrest of
cell
proliferation
Supraphysiological
Mitogenic/
Stress Signals
Oncogenes
Short/dysfunctional
telomeres
(REPLICATIVE SENESCENCE)
The Senescent Phenotype is Not
Simply an Arrest of Cell Proliferation
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
Secreted molecules upregulated by
the senescence response
Proteinases/regulators
MMP-1
MMP-3
Elastase
TIMP-2
PAI-1
Alter tissue
structure
Growth Factors/regulators
EGF
Heregulin
IGFBP-3
IGFBP-4
Alter cell
proliferation
Cytokines
TGF-β
IL-1
IL-6
GRO(KC)
MIP-1
Alter cell
motility,
inflammation
"In itia te d" Cell
YOUNG TIS S UE
EP ITHELIUM
B as e me nt Mem bra ne
S TROMA
AGING ?
S e ne s c e nt
Epithe lia l Ce ll
Ne op las tic
Growth
OLD TIS S UE
EPITHELIUM
B a s e m en t Me mb ra ne
S TROMA
De g ra da tiv e & inflam m ato ry
mo le cu le s , g ro wth fac to rs , e tc
S en es c en t Fibro blas t
Testing the hypothesis that cellular
senescence is antagonistically pleiotropic
Do senescent cells exist and
accumulate with age in vivo?
Goberdhan Dimri
Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE,
Linskens M, Rubelj I, Pereira-Smith O, Peacocke M, Campisi J
(1995) Proc Natl Acad Sci USA 92: 9363-9367
Senescent Cells Accumulate In Vivo
With Increasing Age
Skin
Retina
Liver
Spleen
At Sites of Age-Related Pathology
Venous ulcers
Atherosclerotic plaques
Benign prostatic hyperplasia
Preneoplastic hepatic lesions
Testing the hypothesis that cellular
senescence is antagonistically pleiotropic
Do gatekeeper tumor suppressor
genes accelerate aging?
Larry Donehower
Heide Scrable
Tyner et al., p53 mutant mice that display early aging-associated
phenotypes. Nature 415:45 (2002)
Maier et al., Modulation of mammalian life span by the short form of p53.
Genes Dev 18: 306 (2004)
p53 a quintessential gatekeeper tumor suppressor gene
Transcription factor
(activation and repression of multiple target genes)
Binds DNA as a tetramer
(Donehower/Scrable mutant/short forms thought to
assemble mixed tetramers)
Mixed tetramers “hyperactive”
(hyper-transcriptional activation and/or repression, or
altered spectrum of target genes
“Hyperactive” p53
Donehower mouse: cancer-free but
prematurely aged!
Enhanced apoptotic response to damage
(published)
More senescent cells in tissues of mutant mice
(unpublished)
Scrable mouse: small size, cancer-free but
prematurely aged!
Enhanced senescence owing to supraphysiological
IGF-1 signaling
(unpublished)
p53
+p44
Hyperactive
p53
Altered p53-dependent
gene expression
IGF-1
signaling
p21
Sustained ERK
Cell Cycle Arrest
Senescence
Small Size, Tumor
Suppression
AGING
Testing the hypothesis that cellular
senescence is antagonistically pleiotropic
Do senescent cells facilitate
age-related pathology?
(CANCER)
Ana Krtolica
Simona Parrinello
Krtolica A, Parrinello S, Lockett S, Desprez P, Campisi J
(2001) Proc Natl Acad Sci USA 98: 12072-12077
Senescent Fibroblasts Stimulate the Proliferation of
Premalignant Epithelial Cells
Presenescent
Senescent
Human Fibroblasts (WI-38)
HaCAT
Human Keratinocytes
SCp2
Mouse Mammary
S1
Human Mammary
Senescent Fibroblasts Stimulate Tumorigenesis
of Premalignant Epithelial Cells In Vivo
100
SCp2 cells alone
Tumor size (mm3 x 10)
0
200
100
+ Presenescent
Fibroblasts
0
200
+ Senescent
Fibroblasts
100
0
40
80
120
Days
Testing the hypothesis that cellular
senescence is antagonistically pleiotropic
Do senescent cells disrupt
normal tissue function?
Simona Parrinello
Ana Krtolica
Jean-Philippe Coppe
Three dimensional cultures to study
tissue structure and function:
Human and mouse mammary epithelial cells
organize into physiological alveoli when
cultured with appropriate components in 3D
Morphological organization
Functional differentiation
Senescent fibroblasts inhibit morphological
and functional differentiation
BM + PreS Fb
BM + Sen Fb
Pre-S Fb Sen Fb
β-casein
E-cadherin
β-casein
DAPI
Senescent fibroblasts derange mammary
morphogenesis
Presenescent fibroblasts
Senescent fibroblasts
Primary duct
Secondary duct
Number
Core Area
Core
PRIMARY
SECONDARY
TERTIARY
Cellular senescence, a tumor
suppressor mechanism,
prevents cancer early in life.
Late in life, accumulation of senescent
cells can disrupt normal tissue
structure and function.
Accumulated senescent cells may synergize
with accumulated mutations
to promote cancer and age-related
tissue dysfunction.
Can senescent phenotypes be reversed?
Christian Beausejour, Ana Krtolica, Francesco Galimi, Masashi Narita,
Scott Lowe, Paul Yaswen
(2003) EMBO J 22: 4212-4222
Lentiviruses ---> 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)
ARF
p16
MDM2
p53
CDK4
pRB
Replicatively
Senescent
WI-38
Replicatively
Senescent
BJ
(fetal lung fb)
(foreskin fb)
+ Lenti-GSE (inactivate p53)
No proliferation
20 Doublings
% LN
100
S-WI
80
60
40
% GROWTH: 0
CDK4+GSE
CDK4
LgTK1
GSE+LgT
0
GFP
hTERT
GSE
LgT
20
0 <1 <1 <1 <1 0 <1
S-BJ rescued
S-BJ
80
60
40
20
LgTK1
GSE+LgT
CDK4
GFP
hTERT
GSE
LgT
0
Population doubling
% LN
100
25
0
0 >90 60 40 90 20*
(CRISIS)
LgT
20
LgTK1
CDK4
15
LgT, LgT[K1]
10
5
CDK4m
0
0
% GROWTH:
GSE
GSE
20
40
60
80
100
Days post infection
On the horizon …...
• Molecular strategies to eliminate
(or reverse the phenotype of)
senescent cells
• Cell based therapies (stem cells)
to replace senescent cells or cells lost
through apoptosis in
degenerated tissues
Aging and Tumor Suppression
Aging Phenotypes
Cancer
Gatekeeper
Tumor Suppressors
Can tumor suppression and aging
be uncoupled??
Jean Philippe Coppe
Joshua Goldstein
Ana Krtolica
Francis Rodier
Simona Parinello
Christian Beausejour - Sangamo
Pierre Desprez -CPMC
Goberdhan Dimri - NW U
Francesco Galimi/Inder Verma - Salk
Steve Lockett - LBNL/NCI
Masa Narita/Scott Lowe - CSH
Enrique Samper/Simon Melov - Buck
Carlos Ortiz de Solorano - LBNL
Paul Yaswen - LBNL