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Cellular Senescence What is it? What causes it? Why is it important (cancer and aging)?. Cellular Senescence What is it? Response of normal cells to potentially cancer-causing events The senescence response is an anti-cancer mechanisms that prevents

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Presentation Transcript
slide1

Cellular Senescence

What is it?

What causes it?

Why is it important

(cancer and aging)?

slide2

Cellular Senescence

What is it?

Response of normal cells to

potentially cancer-causing events

The senescence response is an

anti-cancer mechanisms that prevents

the proliferation (growth) of damaged or

dysfunctional cells (potential cancer cells)

slide3

First description: the Hayflick limit

Finite

Replicative

Life Span

"Mortal"

Infinite

Replicative

Life Span

"Immortal"

Proliferative capacity

Number of cell divisions

EXCEPTIONS

Germ line

Early embryonic cells (stem cells)

Many tumor cells

What happens when cells exhaust their replicative life span?

slide4

What happens when cells exhaust their replicative life span?

REPLICATIVE SENESCENCE

  • Irreversible arrest of cell proliferation
  • (universal)
  • Resistance to apoptosis (lecture on January 31)
  • (certain cell types)
  • Altered function
  • (universal but cell type specific)

THE SENESCENT PHENOTYPE

slide5

Cellular Senescence

What causes it?

(what causes the senescent phenotype?)

Cell proliferation (replicative senescence)

= TELOMERE SHORTENING

(lecture on February 26th)

DNA damage

Oncogene expression

Supermitogenic/stress signals

What do inducers of the senescent

phenotype have in common?

slide6

Inducers of cellular senescence

Strong mitogens/

stress

Cell proliferation

(short telomeres)

DNA damage

Oncogenes

Potential Cancer Causing Events

Normal cells

('mortal')

'Immortal' cells

(precancerous)

Transformation

Cell senescence

Apoptosis

Tumor suppressor mechanisms

slide7

Cellular Senescence

A crucial tumor suppressor mechanism

  • Induced by potentially oncogenic events
  • Most tumor cells are replicatively immortal
  • Many oncogenic mutations allow cells to bypass
  • the senescence response
  • Senescence is controlled by the two most important
  • tumor suppressor genes -- p53 and pRB
  • Mice with cells that do not senesce die young
  • of cancer
slide8

Cancer

Caused by genetic (mutations) and

epigenetic (tissue environment) events

slide9

Cancer: genetic events

  • Activation of oncogenes
  • (continuous "go" signal)
  • Inactivation of tumor suppressor genes
  • (removes "stop" signal)
  • Inactivation of tumor suppressor genes encoding
  • p53 and pRB proteins = most common
slide10

p53 and pRB proteins

  • Nuclear proteins controlled by complex pathways
  • (upstream regulators and downstream effectors)
  • Control expression of other genes
  • Halt cell proliferation in response to inducers
  • of senescence
  • Crucial for allowing normal cells to sense and respond

to senescence signals

slide11

Cellular Senescence

An important tumor suppressor mechanism

What does cellular senescence

have to do with aging?

Senescent cells have altered functions

Aging is a consequence of the declining force

of natural selection with age

The senescence response may be an example of

evolutionary antagonistic pleiotropy

slide12

Aging before cell phones ……

Modern, protected

environment

(very VERY recent)

100%

Natural environment: predators,

infections, external hazards, etc

Survivors

Most of

human

evolution

AGE

Antagonistic pleiotropy:

Some traits selected to optimize fitness in young

organisms can have unselected bad

effects in old organisms

(what's good for you when you're young may be

bad for you when you're old)

slide13

Antagonistic pleiotropy

Cellular senescence

Functional changes

unselected, deleterious

Selected for tumor

suppression (growth arrest)

FUNCTIONAL CHANGES ASSOCIATED WITH

CELLULAR SENESCENCE:

Secretion of molecules that can be detrimental to

tissues if not controlled

Senescent fibroblasts secrete proteases, growth factors,

inflammatory cytokines

slide14

Cellular senescence and aging

  • Cells from old donors divide less often than
  • cells from young donors
  • Cells from short-lived species are more sensitive to
  • senescence-inducers, particularly oxidative stress, than
  • cells from long-lived species
  • Cells from donors with premature aging syndromes
  • senesce more readily than cells from normal donors
  • Senescent cells (expressing a senescence marker)
  • accumulate with age and at sites of age-related
  • pathology, including hyperproliferative diseases
slide15

Cellular senescence: Markers in culture and in vivo

p16 expression

Heterochromatic foci

Telomeric-DNA damage foci

DNA damage foci

Human skin,

stained for SA-Bgal

Dimri et al., Proc Natl Acad Sci USA, 1995

slide16

Senescent Cells Accumulate In Vivo

With Increasing Age

Human, rodent and primate

skin, retina, liver, spleen, aorta, kidney, etc.

At Sites of Age-Related Pathology

Venous ulcers

Atherosclerotic plaques

Arthritic joints

Benign prostatic hyperplasia

Preneoplastic lesions

slide17

Senescent cells secrete many inflammatory

cytokines (e.g., IL6, IL8), growth factors

(e.g., PDGF, heregulin), proteases

(e.g., MMPs)

SENESCENT SECRETORY PHENOTYPE

Many similarities among fibroblasts induced to

senesce by different stimuli and among fibroblasts

from different tissues and donor ages

slide18

Senescent cells can strongly alter

tissue microenvironments

May contribute to age-related

declines in tissue structure and function, and

age related disease

senescent fibroblasts disrupt morphological and functional differentiation of epithelial cells
Senescent fibroblasts disrupt morphological and functional differentiation of epithelial cells

BM + PreS Fb BM + Sen Fb

Pre-S Fb Sen Fb

b-casein

E-cadherin

b-caseinDAPI

Parrinello et al., J Cell Sci, 2005

slide21

Cellular senescence, aging … and cancer

WHAT CAUSES CANCER?

Mutations, mutations, mutations ….

A permissive tissue**

(mutations, including potentially cancer-

causing mutations, accumulate with age,

starting from early ages)

slide22

Epithelial

Cells

Fibroblasts

slide23

CONCLUSIONS

The senescence response is a permanent cell growth

arrest that prevents dysfunctional or damaged (potentially

cancerous) cells from proliferating =

Tumor suppressor mechanism

The senescence response may be an example of

evolutionary anagonistic pleiotropy -- protecting young

organisms from cancer but contributing to aging, age-

related disease and (ironically) late life cancer

at old ages