Download Cellular response to stress

UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
Patrice Lassus
Institut de Génétique Moléculaire de Montpellier (CNRS)
“HCV and Cancer”
[email protected]
04 67 34 35 96 56
Cellular response to stress
UE GMBP 321- Principles of Cancer Biology
Senescence, Apoptosis (20-10-2014)!
I- General Introduction
-Definition/concepts!
-Examples!
II- Cellular stress
-Examples!
-Mechanisms / Role in cancer!
III- What we do in the lab…
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
I- What is stress?
Some definitions: !
!
Stress is a condition / an event that is perceived by the organism / the cell as a threat to its
homeostasis.!
!
Homeostasis represents the equilibrium in which the physiological functions are optimum for
the organism /the cells.!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
I- What is stress?
Stress at the organism level:!
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Physiological stress !
!
Psychological stress!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
I- What is stress?
Stress examples at the organism level:!
!
Physiological stress: !
!
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Heat!
Cold!
Sugar level!
Oxygen level!
Infection!
Fear!
!
Psychological stress!
STRESS
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
I- What is stress?
Stress examples at the organism level:!
STRESS
!
Physiological stress: !
!
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Heat: Sweating
Cold: Shivering
Sugar level: change in hormone balance /
glycogenolysis-gluconeogenesis!
Oxygen level: Ventilation rate / Vessels
constriction-dilatation!
Infection: Immune system activation!
Fear: Fight or flight!
Psychological stress!
Sensors
Specific
RESPONSE
ADAPTATION
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
I- What is stress?
STRESS
Stress response is a fundamental survival mechanism!
!
!
What happens if stress is not well managed?!
Sensors
Specific
RESPONSE
ADAPTATION
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
I- What is stress?
STRESS
Stress response is a fundamental survival mechanism!
!
What happens if stress is not well managed?!
-  Stress signal too strong/ too long!
-  Response not well adpated!
Sensors
!
!
Specific
RESPONSE
ADAPTATION
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
I- What is stress?
STRESS
Stress response is a fundamental survival mechanism!
!
What happens if stress is not well managed?!
-  Stress signal too strong/ too long!
-  Response not well adpated!
Sensors
!
!
Specific
RESPONSE
ADAPTATION
Weak/sick/dead
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
II- Is stress a good thing?
!
Too much stress is obviously not good.. However…!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
II- Is stress a good thing?
Too much stress is obviously not good.. However…!
!
Stress is part of evolution.!
New environment
STRESS
Mutations / adaptation
no adaptation
Selection / Survival
Disadvantage / Death
Bases of
Darwinian
Evolution!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
I- Introduction
Cellular response to stress
I- What is stress?
Stress response is a fundamental survival mechanism!
!
Stress response is an adaptative mechanism that contributes to the evolutionary process!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / introduction
Organismal stress <–> Cellular stress!
Many similarities
- Same Signalling!
STRESS
Sensors
Specific
RESPONSE
ADAPTATION
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / introduction
Organismal stress <–> Cellular stress!
Many similarities
- Common stimuli!
!
At the organism level:!
-  Temperature!
-  Sugar level!
-  Oxygen level!
-  Infection!
-  Fear!
At the Cellular level:!
-  Temperature!
-  Nutrient!
-  Oxygen level!
-  Infection!
-  Genomic /protein /lipidic damage!
-  Mechanical!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / introduction
Organismal stress <–> Cellular stress!
Many similarities
- Same concept for cancer cells!
New environment
STRESS
Mutations / adaptation
no adaptation
Selection / Survival
Disadvantage / Death
Bases of
Darwinian
Evolution!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / introduction
Uncontrolled growth
of cancer cells
Organismal stress <–> Cellular stress!
Many similarities
- Same concept for cancer cells!
Abnormal /
Rapidly evolving
environment
New environment
STRESS
High level of
STRESS
Mutations / adaptation
no adaptation
Selection / Survival
Disadvantage / Death
Bases of
Darwinian
Evolution!
High!
Selection
pressure!
Mutations / adaptation
Selection / Survival /
Agressiveness
Stress response is fundamental to tumor progression
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- 
- 
- 
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Temperature!
Nutrient!
Genomic /protein / lipidic damage!
Oxygen level!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- Temperature (heat)!
Organisms have adapted to growth temperatures from the freezing point of water to 113 C There is not a general optimal temperature for all organisms but a specific one for each specie
For all living organisms, temperatures only moderately above the respective optimum growth
temperature represent a challenging problem for survival. Heat shock response is very sensitive and is triggered by a temperature increase of just a few
degrees. UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- Temperature (heat)!
Prolonged Heat shock induces profound changes in cells:
-  Stress fibers / defect in the cytoskeleton
-  Miss localization of organelles -  Fragmentation of Golgi /ER
-  Drop in ATP levels
-  Aggregation of ribosomes
-  RNA splicing affected
Heat
Protein
Unfolding
Denaturation
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- Temperature (heat)!
Heat
HSF1
HSPs
HSPs
chaperone
complexes
Folding / refolding
Prevention of aggregates
Protein
Unfolding / denaturation
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- Temperature
(heat)!
Heat
Heat
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- Nutrients (glucose / amino acids)!
Nutrients
mTOR
pathway
Autophagy
Cell
proliferation /
size
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- Nutrients (glucose / amino acids)!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- Nutrients (glucose / amino acids)!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- Cellular damages: example of DNA!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen!
Oxygen is essentiel for cell survival.
Oxygen is an essentiel part of the reactions that give energy to the cells.
These reactions take place in the mitochondria at the level of the electron transport chain.
ETC uses oxygen to produce energy in the form of ATP UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen!
Because it is essential, modulation of oxygen levels are a source of stress
Two types of stress related to oxygen can be distinguished:
-Oxygen deprivation: Hypoxia
-Stress generated by oxygen byproducts: Oxidative stress
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
Oxygen is used in different types of reactions that give rise to different highly reactive byproducts called:
ROS: Reactive Oxygen Species
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
ROS are produced mainly in the mitochondria
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
ROS can also be genenrated by other organelles or cytosolic enzymes.
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
ROS are highly reactive and can be harmful for cells
ROS
Lipids
protein
DNA
ROS are considered as powerful mutagens!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
ROS can be induced by several stimuli including oncogenic events.
Radiation
Chemo drugs
Oncogenes
Metabolic defects
Inflammation
ROS
Lipids
protein
DNA
ROS are considered as powerful mutagens!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
ROS levels need to be kept low: Role of scavengers
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
ROS levels too high: Role of NRF2
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
ROS levels too high: Role of NRF2
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
ROS levels too high: Role of NRF2
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
NRF2
Radiation
Chemo drugs
Oncogenes
Metabolic defects
Inflammation
ROS
Lipids
protein
DNA
ROS are considered as powerful mutagens!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
- Is NRF2/KEAP1 involved in cancer?!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
- Is NRF2/KEAP1 involved in cancer?!
In light of its anti-oxidant activity, NRF2 should be considered as
a powerful tumor suppressor gene.. !
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
- Is NRF2/KEAP1 involved in cancer?!
In light of its anti-oxidant activity, NRF2 should be considered as
a powerful tumor suppressor gene.. !
!
!
It is a bit more complicated than that…!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
-  Is NRF2 involved in cancer?!
Tumors sequencing revealed that:
Both Keap1/ NRF2 are frequently mutated.
Surprisingly, mutations on keap1 are mostly inactivating
while mutation on NRF2 are activating..
NRF2 could then be an oncogene?
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
-  Can NRF2 act as an oncogene?!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
-  Is NRF2 an oncogene? Yes!!!
How do we explain this paradox ?!
Apoptosis
Senescence
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
-  Is NRF2 an oncogene? Yes!!!
How do we explain this paradox ?!
Apoptosis
Senescence
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
-  One might ask then…!
Are anti-oxidants bad?!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
-  One might ask then…!
Are anti-oxidants bad?!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Oxidative stress!
-  One might ask then…!
Are anti-oxidants bad?!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia!
-Oxygen deprivation: Hypoxia
Because oxygen is essential, decreases of oxygen levels are a source of major stress
That trigger a very important and complex response
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia!
STRESS
Hypoxia
Sensors
PHDs
Specific
RESPONSE
HIF Transcription
factors
ADAPTATION
ADAPTATION
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia!
Hif (hypoxia inducible factor)!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia!
Hif (hypoxia induced factor)!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia!
Complex adaptative response: 1-Metabolic reprogramming!
The lack of oxygen inhibits oxydative phosphorylation in the mitochondria. To sustain energy, cells switch their metabolism to glycolysis UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
!
Hypoxia !
-  1-Metabolic reprogramming!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia!
Complex adaptative response: 2-Angiogenesis!
The lack of oxygen induces angiogenesis as a survival mechanism in order to improve and increase oxygen supply through blood vessels.
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia!
Complex adaptative response: 3-Migration / invasion!
Because the hypoxic environment is far from being optimal, hypoxic cells will try to move away from it toward
a more oxygenated environment
ECM degradation:
MMPs
Lowering extracellular pH
HIF
Induction of EMT:
Induction of EMT factors:
Twist, Snail
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia!
Complex adaptative response:!
HIF
METABOLIC
REPROGRAMING
ANGIOGENESIS
MIGRATION
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia / Cancer!
-  Is Hypoxia involved in cancer?!
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia / Cancer!
Hypoxia is found in virtually all solid
tumors
Cancer cells grow quickly. The more the
tumor grows the more there will be cells
located far away from vessels and from
blood supply.
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia / Cancer!
Hif1a is now considered as a powerful
oncogene.
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia / Cancer!
Hypoxia induces many other
phenotypes in cancer cells.
All theses phenotype are traits
of aggressiveness.
Hypoxia is an environment of
high selective pressure that is
responsible for the generation
and the selection of aggressive
cancer cells
Hypoxia is this very important
for tumor malignancy
UE Principles of Cancer Biology
Cellular stress (18-11-2015)!
II- Cellular stress
Cellular response to stress
I- Cellular stress / examples
- The case of oxygen: Hypoxia / Cancer!
Anti-angiogenic therapies
Rational: blocking angiogenesis in tumor to starve them from oxygen / nutrients
Improve overall survival in some cases but aggravates the outcome in others!
AA therapies block blood
supply.
Consequence is…induction of
hypoxia
Higher degree of hypoxia means
Increased selection pressure
and appearance of even more
agressive cancer cells.