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?

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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