Download 3.2.2.2 Cellular targets Sabatier

Cellular Targets and Transmission
of radiation-induced damage
aging
L.Sabatier - Research needs and strategic directions –Brussels June 20-21 2007
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Progeny of irradiated cells :cellular
targets
Senescence
™ Endothelial cells
™ Fibroblats – keratinocytes
™ mesenchymal stem cells
Keratinocytes
™ Human mammary epithelial cells
From lymphocytes-fibroblasts
™ ….
To epithelial cells
Co-culture/3D
Normal cells-> pretumoral™->tumor
cells
• Low doses
3D- co-culture
Tissue ™ ->0,01 Gy
HUMAN ™ -> 0,2 mGy/mn
15
10
Senescent
20
Agonescent
25
young
Population doublings
30
Emergent
•
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0
10
20
30
40
50
Days
L.Sabatier - Research needs and strategic directions –Brussels June 20-21 2007
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IRRADIATION
γ / heavy ions
quantification
quality
DNA STRAND BREAKS
DOUBLE
SINGLE
CELL DEATH
CHROMOSOMAL DAMAGES
MUTATIONS
ter. del
inter. del
ring
peri. inv
para.inv
CELL
TRANSFORMATION
TUMOUR
2
dicentric
reciprocal translocation
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2
complex rearrangement
2
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RADIATION-INDUCED
CHROMOSOMAL
INSTABILITY
Cancer cells :
clonal evolution from a
single cell
chromosome imbalances
chromosome
rearrangements
Sporadic end-to-end
fusions
Probability to induce
specific balanced translocation
at low dose?
F.Mitelman, 2007
Chromosome rearrangements in radiation-induced solid tumors
Several chromosome rearrangements profiles
in solid tumours
-Balanced translocations
- -clonal evolution
-Norla Karyotypes
MMR mutations
- -clonal evolution
- Gain of chromosomes
Gene dosage -oncogene
- -clonal evolution
One chromosome rearrangement profile
in solid tumours :very smal cohort
-Non reciprocal translocations
- deletions
- amplifications
-Loss of chromosomes
-Loss of tumour suppressor genes
-Non reciprocal translocations
- deletions
- amplifications
-Loss of chromosomes
-Loss of tumour suppressor genes
- Gain of chromosomes
-Endoreplication
--clonal evolution
- Gain of chromosomes
-Endoreplication
--clonal evolution
New tools => tumor caracterisation
CGH
CISH-FISH
Systems biology « omics »
Specificity of
Radiation-Induced tumors?
Padilla-Nash et al., Genes, Chromosomes & Cancer. 1999
non differentiated fibrosarcoma
Chauveinc et al, Cancer Genet Cytogenet, 1999
LOH : secondary event
The large majority of these radiation-induced mutations are recessive i.e
will remain silent until the occurrence of a mutation on the second allele (highly
improbable at low dose) or LOH.
Telomere
Centromere
Chromosome segregation
Epigenetic modifications
Seek for mechanisms
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*
L.Sabatier - Research needs and strategic directions –Brussels June 20-21 2007
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Immortalisation
Telomere maintenance
46 chromosomes
92 telomeres
10% => Telomere loss
Mis seggregation
aneuploidy
Loss/gain
of chromosome arm
Cell death
« amplificator event »
Proliferative advantage
Unmasked mutations
Probability of a radiation
induced secund gene damage
«0»
35 000 genes
Mutation events
Mainly recessive
Life and aging
Endogenous stress
Irradiation
L.Sabatier - Research needs and strategic directions –Brussels June 20-21 2007
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Hypothetical scheme of radiation
oncogenesis (solid tumors)
a)induction of recessive gene mutations (direct effect of radiations)
b)accumulation of genomic alteration in the irradiated tissues with aging and
proliferation of irradiated and non irradiated cells
c) unmasking, amplification… of radiation induced or pre-existing mutations
d)loss of tumour suppressor functions (aneuploidy),
e)gain of proliferative advantage
f)on going instability: cycles of b-e steps
g)initiation and progression of multistage carcinogenesis.
Cell to cell interactions, Tissue control and Low dose effect will differ
according to cell progression in the multistep carcinogenesis
=>tumor will arise from a single cell
L.Sabatier - Research needs and strategic directions –Brussels June 20-21 2007
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Low dose effect
Irradiated tissue can remain healthy until aging , then…
Low dose effect on secund event
and interplay with cellular aging
•
™
Mechanisms of long term induction of aneuploidy
=> LOH
™
Genomic instability
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•
IR
Aging process –ROS-
Transmission
Not an unique process
Damage
Cell type
Cell stage
Tissue
Individual
Individual radiosensitivity
Increased amount of mutations???
=> ability to unmask recessive damage
=> risk
•
Caracterisation of human radiation induced tumeurs
•
HUMAN STUDIES
™
™
Senescence barriers
Chromosome morphology
L.Sabatier - Research needs and strategic directions –Brussels June 20-21 2007
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Cross-fertilisation
•
Epidemiology :
•
Characterization of induced tumours/ balanced rearrangements/ latency of occurrence
™
™
™
Balanced translocation
Chromosome imbalance
Aging/tumor occurrence
•
Modelling :
•
Is possible to take into account the diversity of the carcinogenesis processes into
mathematical modelling? (ie oncogene activation like Brukitt lymphoma, multistep
carcinogenesis...) and modulate the role of chromosome aberrations (radiation
induced/acquired during aging) in each?
•
Could the theoreticians model the relationship between aging and carcinogenesis including
replicative senescence and reactivation of telomere maintenance process in immortal cells
and is it possible to use such models to identify which steps are modulated by radiation?
L.Sabatier - Research needs and strategic directions –Brussels June 20-21 2007
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