LE introduction to the course
Cell stress = alterations in the internal and external cell environment
• Can lead to dysfunction of tissue level, then organ level and then system level and here
you can see death
• Mechanical stress = injury
• Infection
• Hyperthermia
• Hypothermia
• Toxins
• Storage disorders (genetic disorders, not gettting rid of your garbage)
• Energy shortage (hypoxia, mitochondrial disorders, starvation)
• Living and ageing
Reaction to stress
• When adaptation is possible > cell survival
o Atrophy = reduction in size and function of cell
• Saving energy
o Hypertrophy = increase in cell size and function
• In heart, it can effect pumping or block entry of blood
o Hyperplasia = increase in cell number
• Always seen in prostate
• Age-related
• Specific cause unclear
• Can lead to cancer
o Metaplasia = change in differentiation state
• Adaptation in chronic acid exposure (example)
• Stratified squamous epithelial > simple columnar epithelium
• Occurence of goblet cells (normally only in intestine)
• One step to malignant stage
o Dysplasia = disorganized tissue structure
• Tissue looses normal architecture
• Premalignant: probably will lead to cancer if it is not monitored
• Cellular senescence = zombie cells, cells are alive but not in the normal way (stage
between survival and death)
o Do more harm then good
• When adaptation is impossible > cell death > inflammation (key player in process)
o Apoptosis
o Necrosis
o Necroptosis
o Ferroptosis
o Autophagy
o Pyroptosis
Labile, stabile and permanent cells
• Labile cell
o continuously cycle until they get a signal to go out due to damage
o When there is damage, they will go in apoptosis
• Stable cells
o are effectively in G0, not interested in replication, but if the need arises, then they
can still enter the cell cycle again (quiescent cells) (out in G0 and in in G1 phase)
, • Permanent cells (neurons, cardiac myocytes
o If you loose them, extremely low potential to regenerate these cells (out in G1
phase)
Cellular senescence
• Cell cycle arrest is irreversible
• Apoptosis resistance, benefit of keeping cell alives, they can signal to environment for
wound healing
o For signaling they use SASP (senescence associated secretory phenotype
• Secretion cytokines and chemokines
• Can be caused by
o (sublethal) oxidative stress > sublethal due to the zombie state and a suboptimal
function
o (sublethal) DNA damage
o Replicative stress (telomere shortening / dysfunction)
o Oncogene activation / defective apoptotic signaling
• Senescence works as tumor suppressor mechanism, because it does not
proliferate anymore
• The senescent cell burden accumulates strongly with age
o Increased rate of damage and imparied immune-mediated removal play
important roles
o The older the more persistent damage
o Immune cells play a part on removing these cells
,The cell cycle in cancer
• Cancer is a process of uncontrolled cell proliferation
o Check on cell cycle disturbed > p53 / RB system
o Regulation of apoptosis is disturbed > bcl system, role of mitochondria
o Metabolism is disrupted > (VHL, IDH)
• In cancer there is more proliferation then apoptosis, while this is normally equally
divided
Cell cycle visualization: Cdt1 is expressed in G1 but degraded by geminin from S-phase on
• Cdt1 = licensing factor, makes sure that MCM binds to specific part in DNA, can not have
multiple copies in cell cycle
• Geminin = DNA replication licensing inhibitor, active from S phase onwards
• MCM = DNA helicas > crucial for DNA replication and elongation > binds to specific part
on the DNA
, By giving both proteins a specific label you can see in which phase of the cell cycle you are
• Looking at an agent that blocks cell cycel in G1: cell gets stuck in G1. This causes stress
and eventually will lead to apoptosis
• In the S-phase Cdt1 is degraded in by geminin
• FUCCI Cdt1-orang/geminin-green
Epigenetic modification: HDAC (histone deacetylation) inhibitors
• HDAC decide which genes are on by open or closed chromatins
• VPA can cause growth arrest and induce differentiation of transformed cells in culture
through HDAC inhibition
o Apoptosis induction through upregulation of pro-apoptotic proteins
• This can say something about how you can visualize the processes in a cell
Cell stress = alterations in the internal and external cell environment
• Can lead to dysfunction of tissue level, then organ level and then system level and here
you can see death
• Mechanical stress = injury
• Infection
• Hyperthermia
• Hypothermia
• Toxins
• Storage disorders (genetic disorders, not gettting rid of your garbage)
• Energy shortage (hypoxia, mitochondrial disorders, starvation)
• Living and ageing
Reaction to stress
• When adaptation is possible > cell survival
o Atrophy = reduction in size and function of cell
• Saving energy
o Hypertrophy = increase in cell size and function
• In heart, it can effect pumping or block entry of blood
o Hyperplasia = increase in cell number
• Always seen in prostate
• Age-related
• Specific cause unclear
• Can lead to cancer
o Metaplasia = change in differentiation state
• Adaptation in chronic acid exposure (example)
• Stratified squamous epithelial > simple columnar epithelium
• Occurence of goblet cells (normally only in intestine)
• One step to malignant stage
o Dysplasia = disorganized tissue structure
• Tissue looses normal architecture
• Premalignant: probably will lead to cancer if it is not monitored
• Cellular senescence = zombie cells, cells are alive but not in the normal way (stage
between survival and death)
o Do more harm then good
• When adaptation is impossible > cell death > inflammation (key player in process)
o Apoptosis
o Necrosis
o Necroptosis
o Ferroptosis
o Autophagy
o Pyroptosis
Labile, stabile and permanent cells
• Labile cell
o continuously cycle until they get a signal to go out due to damage
o When there is damage, they will go in apoptosis
• Stable cells
o are effectively in G0, not interested in replication, but if the need arises, then they
can still enter the cell cycle again (quiescent cells) (out in G0 and in in G1 phase)
, • Permanent cells (neurons, cardiac myocytes
o If you loose them, extremely low potential to regenerate these cells (out in G1
phase)
Cellular senescence
• Cell cycle arrest is irreversible
• Apoptosis resistance, benefit of keeping cell alives, they can signal to environment for
wound healing
o For signaling they use SASP (senescence associated secretory phenotype
• Secretion cytokines and chemokines
• Can be caused by
o (sublethal) oxidative stress > sublethal due to the zombie state and a suboptimal
function
o (sublethal) DNA damage
o Replicative stress (telomere shortening / dysfunction)
o Oncogene activation / defective apoptotic signaling
• Senescence works as tumor suppressor mechanism, because it does not
proliferate anymore
• The senescent cell burden accumulates strongly with age
o Increased rate of damage and imparied immune-mediated removal play
important roles
o The older the more persistent damage
o Immune cells play a part on removing these cells
,The cell cycle in cancer
• Cancer is a process of uncontrolled cell proliferation
o Check on cell cycle disturbed > p53 / RB system
o Regulation of apoptosis is disturbed > bcl system, role of mitochondria
o Metabolism is disrupted > (VHL, IDH)
• In cancer there is more proliferation then apoptosis, while this is normally equally
divided
Cell cycle visualization: Cdt1 is expressed in G1 but degraded by geminin from S-phase on
• Cdt1 = licensing factor, makes sure that MCM binds to specific part in DNA, can not have
multiple copies in cell cycle
• Geminin = DNA replication licensing inhibitor, active from S phase onwards
• MCM = DNA helicas > crucial for DNA replication and elongation > binds to specific part
on the DNA
, By giving both proteins a specific label you can see in which phase of the cell cycle you are
• Looking at an agent that blocks cell cycel in G1: cell gets stuck in G1. This causes stress
and eventually will lead to apoptosis
• In the S-phase Cdt1 is degraded in by geminin
• FUCCI Cdt1-orang/geminin-green
Epigenetic modification: HDAC (histone deacetylation) inhibitors
• HDAC decide which genes are on by open or closed chromatins
• VPA can cause growth arrest and induce differentiation of transformed cells in culture
through HDAC inhibition
o Apoptosis induction through upregulation of pro-apoptotic proteins
• This can say something about how you can visualize the processes in a cell
