Hallmarks of Cancer: Resistance to Cell Death(Types of cell death and apoptosis resistance mechanisms)
Prof. Dr. rer. nat. Anna Trauzold
Institut for Experimental Cancer Research
Aims of the lecture
After attending this lecture, students will be able to:
- define the terms apoptosis, necrosis, necroptosis, autophagy
- describe the mechanisms of apoptotic cell death (important points and terms:
caspases, intrinsic triggers, extrinsic triggers, type I/type II cells, death receptors,
dependence receptors)
- describe the role of death receptors in cancer (TRAIL receptors)
- name and define the potential apoptosis-resistance mechanisms operating in
tumor cells
- know and understand the mechanisms underlying anti-tumor and tumor-
promoting role of cell death
-apoptosis in anti-tumor therapie
Physiological cell death
• Elimination of infected/injured cells
• Elimination of tumor cells
• Embryogenesis
• Control of the tissue size
• Renewal of epithelia
• Selection (immune system)
(Patho)physiological cell death (too much)
• Cardiovascular diseases (cardiac infarction)
• Radio-/Chemotherapy
• Cirrhosis of the liver
• Neurodegenerative diseases (Morbus Parkinson)
• Infections (HIV, HBV, HCV)
(Patho)physiological cell death (too little)
Hanahan & Weinberg, 2011, Cell 144: 646-674
Efficient induction and successful execution of cell deathis an aim of many anti-tumor therapies
Until recently
Apoptosis vs. Necrosis
programmed vs. accidental
active vs. passive
Belizario et al., 2015, Mediators of Inflammation
DOI: 10.1155/2015/128076.
Programmed
(regulated)
cell deathApoptosis
activation
of caspases
silent death
without
inflammation
and
immune response
Active process Clarke & Smyth, 2007,
Nat. Biotech. 25: 192-3.
„eat me signal“
macrophage
Until recently
Accidental
cell deathNecrosis
cell death
with
inflammation
Passive processClarke & Smyth, 2007,
Nat. Biotech. 25: 192-3.
Until recently
induced by extremely harsh physical conditions
Apoptosis 213 116 256 616 357 271 385 895 180%
Necrosis 256 470 285 844 350 818 369 034 143.8%
Autophagic cell death 8661 14271 32435 38 665 446.4%
Anoikis 885 1156 1663 1801 203.5%
Cornification 759 814 915 939 124%
Mitotic catastrophe 506 654 932 994 196.4%
Necroptosis 106 318 1459 1909 1800,9%
Pyroptosis 82 203 789 1116 136.1%
Entosis 21 37 80 88 419%
Parthanatos 16 30 96 113 706%
Netosis 16 71 377 492 307.5%
Cell death modalities Number of articles in PubMed
Nov. 2011 Nov. 2013 Nov. 2017 Nov. 2018
Cell Death Differ. 2012 Jan;19(1):107-20.
No more valid equation!
Programmed
(regulated)
cell deathApoptosis
activation
of caspases
silent death
without
inflammation
and
immune response
• Existence of other forms of regulated cell death (necroptosis and autophagic cell death)
Programmed
(regulated)
cell deathApoptosis
activation
of caspases
silent death
without
inflammation
and
immune response
No more valid equation!
• Apoptosis can occur also without activation of caspases, caspases can also be activatedin other cell death modalities
• Existence of other forms of regulated cell death (necroptosis and autophagic cell death)
Programmed
(regulated)
cell deathApoptosis
activation
of caspases
silent death
without
inflammation
and
immune response
No more valid equation!
• Apoptosis can occur also without activation of caspases, caspases can also be activatedin other cell death modalities
• Cells dying by apoptosis can induce inflammation and immune response
• Existence of other forms of regulated cell death (necroptosis and autophagic cell death)
Programmed
(regulated)
cell deathApoptosis
activation
of caspases
silent death
without
inflammation
and
immune response
No more valid equation!
Reviewed by Kepp et al., 2011, Cancer Metastasis Rev 30:61-69.
Tumour cells dying after exposure to antracyclins (for example doxorubicin, mitoxantrone),
oxaliplatin or ionizing radiation can induce strong anticancer immune response
Calreticulin (CRT) at the plasma membrane of dying cell
– “eat me signal” for antigen presenting dendritic cells
Priming of
CD4+ and CD8+
lymphocytes,
anti-tumor response
Programmed
(regulated)
cell deathApoptosis
activation
of caspases
silent death
without
inflammation
and
immune response
No more valid equation!
Kroemer et al., 2013, Annu. Rev. Immunol. 31:51-72.
ICD immunogenic cell death; DC, dendritic cell;
CTL, cytotoxic T-cell lymphocytes; CRT, calreticulin
Immunogenic Cell Death (ICD) – determines the long-term success of anticancer therapy
Suboptimal regimens(without inducing ICD)
Alterations in cancer cells(preventing emission of immunogenic signals)
Defects in the immune effectors(abolishing the perception of ICDby the immune system)
All contributeto therapeutic failure
Accidental
cell deathNecrosis
cell death
with
inflammation
In some cases (inhibition of caspases) stimulation of cells with death ligands (CD95, TNFalpha, TRAIL) leads to necrosis = necroptosis – regulated, active process
Passive process
not always!
Programmed
(regulated)
cell deathApoptosis
activation
of caspases
silent death
without
inflammation
and
immune response
No more valid equation!
Necroptosis, parthanatos, oxytosis, ferroptosis, NETosis, pyronecrosis and pyroptosis
Berghe et al., Nat Rev Mol Cell Biol. (2014) ;15(2):135-47.
RIPK1/3: receptor-interacting protein kinase 1/3
MLKL: mixed lineage kinase domain-like
Emerging pathways of regulated necrosis
Tentative forms of regulated necrosis
NecroptosisPyroptosisEntosisParthanatosNetosis
Autophagy: Renovation of cells and tissues
Major intracellular degradation system by which cytoplasmic materialsare delivered to and degraded in the lysosome
The purpose of autophagy is not the simple elimination of materials, instead it serves asdynamic recycling system that produces new building blocks and energyfor cellular renovation and homeostasis
Essential role in:
•metabolic adaptation (starvation)
•intracellular quality control (degradation of damaged mitochondria)
•renovation during development (after fertilization maternal proteins and RNAs are extensively degradedwhile new proteins encoded by the zygotic genome are synthesized)
•differentiation (lineage differentiation: adipocytes, erythrocytes, T-cells)
•Impairment or activation of autophagy contributes to pathogenesis of diverse diseases
Mizushima & Komatsu, Cell 2011, 147: 728-740
Kroemer & Levine, Nat. Rev. Mol. Cell Biol. 2008 Dec;9(12):1004-10
In mammals autophagy is usually a self-
limiting process that protects cells from death
and is essential for tissue homeostasis.
mammalian cells die usually either by
necrosis (necroptosis) or apoptosis.
presence of the autophagosomes usually only
accompany cell death - cell death with
autophagy
real autophagic cell death
There are only few known examples of cell
death that can be prevented by genetic
inhibition of autophagy in mammals
in lower organisms, several developmental
processes
(salivary gland involution in the larvae of
Drosophila, excitotoxic cell death of
Caenorabditis elegans neurons)
Autophagic cell death
Galluzzi et al., Cell Death Differ., 2015 Jan;22(1):58-73.
Regulated cell death
cell death occuring by dedicated molecular machinery,can be inhibited by targeted pharmacologicaland/or genetic intervention
Cell death modalities today
Apoptosis (extrinsic and intrinsic pathways)Autophagic cell death / cell death with autophagyNecroptosis (maybe some other forms) - regulated necrosis
Accidental cell death
cell death triggered by extremely harsh physical conditions,cannot be inhibited by pharmacological and/or genetic manipulations
Necrosis
Programmed cell death – cell death occuring without any exogenous perturbations –hence operating as a physiological program in development or tissue turnover
Apoptosis
Apoptosis
intrinsic
caspase-
-dependent
extrinsic
death receptors dependence receptors
caspase-
-independent
caspase-
-dependent
inducing signal executing machinery
Apoptosis
Apoptosis
intrinsic
caspase-
-dependent
extrinsic
death receptors dependence receptors
caspase-
-independent
caspase-
-dependent
inducing signal executing machinery
Caspases – the motors of Apoptosis
Proteases
Cysteine in active centerCleave proteins after Aspartate(Cysteine Aspartase)
Present in the cytoplasm as inactive forms- Procaspases
Caspases are activated via:
1. autocatalysis2. transactivation by other caspases3. proteolysis by other proteases
(Granzyme B, Cathepsin G)
Initiator caspases
Pro-apoptotic stimulus
Effektor caspases
Caspasecascade
Apoptosis
Caspase – Family
p10p20CARD
p20CARD
p20CARD
p20CARD
p20CARD
p20CARD
p20DEDDED
p20DEDDED
p20N-
p20N-
p20N-
p20CARD
p10
p10
p10
p10
p10
p10
p10
p10
p10
p10
p10
Caspase-1
Caspase-4
Caspase-5Caspase-13
Caspase-2
Caspase-9
Caspase-8
Caspase-10
Caspase-3
Caspase-6
Caspase-7
Caspase-14
InflammationActivation of cytokines
Apoptosis
Differentiation
RegulatoryDomain
CatalyticDomain
CARD, caspase recruitment domain; DED, death effector domain; N, N terminal peptide
Apoptotic Caspases are classified as Initiator- or Effector-Caspases
p10p20CARDp20CARDp20DEDDEDp20DEDDED
p10p10p10
Caspase-2Caspase-9Caspase-8Caspase-10
p20N-p20N-p20N-
p10p10p10
Caspase-3Caspase-6Caspase-7
Initiator-Caspases:
Effector-Caspasen:
CARD, caspase recruitment domain; DED, death effector domain; N, N terminal peptide
p20DEDDEDp20DEDDED
p10p10
cleavage sites
p20
p20p10 p10
Active tetramer cleaves other caspasesand initiates cell death signaling
Effector-Caspases cleave cytoplasmicand nuclear substrates
Cell death
Pro-caspases
Apoptosis
Apoptosis
intrinsic
caspase-
-dependent
extrinsic
death receptors dependence receptors
caspase-
-independent
caspase-
-dependent
inducing signal executing machinery
Intrinsic Apoptosis
Apoptosis
intrinsic
caspase-
-dependent
caspase-
-independent
inducing signal executing machinery
Organelle-specific initiation of cell death
Nucleus – DNA damage, mitotic problems
Mitochondrium – Central regulator of cell death
hypoxia, respiratory chain inhibitors
Conditions that imbalance protein homeostasis (UPR)
Microbial stimuli
ER – UPR
Cytoskeleton – perturbations of the microtubular or actin network
Cellular Stress
Growth factor deprivation
Chemotherapeutics
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
APAF1, apoptotic protease activating factor-1; BAK, BCL2 homologous antagonist/killer; BAX, BCL2-associated protein; BCL2, B-cell
chronic lymphocytic leukemia/lymphoma 2; PUMA, p53-upregulated modulator of apoptosis;
Intrinsic apoptosis
Cellular Stress
Growth factor deprivation
Chemotherapeutics
Chemotherapy
Radiotherapy
Caspase 3, 6, 7
Apoptosis
p53
BAX, BAK
Mitochondria
p53
Caspase 9
DNA damage
PUMA, NOXA
p53
APAF1
Cytochrome c
DNA damage
SMAC/DIABLO
Organelle-specific initiation of cell death
Nucleus
Mitochondrium
ER
Cytoskeleton
inducing signal
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
APAF1, apoptotic protease activating factor-1; BAK, BCL2 homologous antagonist/killer; BAX, BCL2-associated protein; BCL2, B-cell
chronic lymphocytic leukemia/lymphoma 2; PUMA, p53-upregulated modulator of apoptosis;
Intrinsic apoptosis
Cellular Stress
Growth factor deprivation
Chemotherapeutics
Apoptosis
Apoptosis
intrinsic
caspase-
-dependent
extrinsic
death receptors dependence receptors
caspase-
-independent
caspase-
-dependent
inducing signal executing machinery
Extrinsic apoptosis
Activation of effector caspases
Apoptosis
death receptor
death ligand dependence receptor
Dependence receptors have two faces:In the presence of ligand – transduction of a positive signalIn the absence of ligand – induction of apoptosis
All are cleaved by caspasesAll contain an ADD (addiction/dependance domain)After exposition of ADD by receptor cleavage ADD recruits additional caspase-activating complexes
Dependence Receptors
Goldschneider & Mehlen, Oncogene 2010, 1865-1882
Death Receptors
TNF FasL TL1A TRAIL ? NGFEDA1
DR4 DR5 DcR2 DcR1
Cysteine-rich motif
Death domain
TL1, TNF-like cytokine;
EDAR, Ectodermal displasia receptor
EDA1, Ectodysplasin A1
NGF, Nerve growth factor
Physiological function of Death Receptors (CD95 & TRAIL-Rs)
TRAIL-R1/R2
TRAIL
NK
CTL
tumor cellCD95
NK
CTL
TNFRI – mainly inflammation
tu mor
cell
TRAIL-R1/R2
TRAILNK
CTL
tumor cellCD95
CD95L
NK
CTL
CD95L
TRAIL-R1/R2
TRAILNK
CTL
CD95
CD95L
NK
CTL
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
DR, death receptor; DL, death ligand; FADD, Fas-associated death domain;
Caspase 3, 6, 7
Apoptosis
FADDProcaspase 8, 10
Caspase 8, 10
Death receptor-mediated apoptosis
Type I-CellsDISC
DR
DL
DR
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
APAF1, apoptotic protease activating factor-1; BID, BH3-interacting domain death agonist; DR, death receptor; FADD, Fas-
associated death domain;
Caspase 3, 6, 7
Apoptosis
FADDProcaspase 8, 10
Caspase 9
Caspase 8, 10
t-BID
Mitochondria
Cytochrome c
BID
APAF1
DISC
BAX, BAK
Type II-Cells
Death receptor-mediated apoptosis
DR
DL
DR
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
APAF1, apoptotic protease activating factor-1; BAK, BCL2 homologous antagonist/killer; BAX, BCL2-associated protein;; BID, BH3-
interacting domain death agonist; DR, death receptor; FADD, Fas-associated death domain; PUMA, p53-upregulated modulator of
apoptosis;
Caspase 3, 6, 7
Apoptosis
death receptor ligand TRAIL
FADD
Cell-extrinsic
pathway
Procaspase 8, 10
p53p53
Caspase 9
Caspase 8, 10
p53
BAX, BAK
Mitochondria
Chemotherapy
Radiotherapy
DNA damage
PUMA, NOXA
APAF1
Cytochrome c
DNA damage
BID
Cell-intrinsic
pathway
Intrinsic and extrinsic apoptotic pathways are linked
t-BID
TRAIL-R1
TRAIL-R2
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
APAF1, apoptotic protease activating factor-1; BID, BH3-interacting domain death agonist; DR, death receptor; FADD, Fas-
associated death domain;
Each step of the apoptotic pathway is tightly controlled
TRAIL
Caspase 3, 6, 7
Apoptosis
FADD
Procaspase 8, 10
Caspase 9
Caspase 8, 10
t-BID
Mitochondria
Cytochrome c
BID
APAF1
BCL2, BCLXL, MCL1
SMAC/DIABLO
IAP
FLIP
BAX, BAK
DISC
Decoy-Receptors
TRAIL-R1
TRAIL-R2
Decoy-receptors diminish DISC-formation
DcR: Decoy Receptor; OPG: Osteoprotegerin
OPG – soluble Receptor for TRAIL
DcR1 - membrane-anchored TRAIL-R
DcR2 - TRAIL-R with truncated DD
Lemke et al., Cell Death Differ. 2014, 1-15
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
APAF1, apoptotic protease activating factor-1; BID, BH3-interacting domain death agonist; FADD, Fas-associated death domain;
FLIP
Caspase 3, 6, 7
Apoptosis
FADD
extrinsic
pathway
Procaspase 8, 10
Caspase 9
Caspase 8, 10
t-BID
Mitochondria
Cytochrome c
BID
FLIP inhibits DISC-activity
APAF1
BCL2, BCLXL, MCL1
SMAC/DIABLO
IAP
FLIP
BAX, BAK
FLIP – Caspase-8-homologueMutation in active center
DISC
DR
DL
DR
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
APAF1, apoptotic protease activating factor-1; BID, BH3-interacting domain death agonist; DR, death receptor; FADD, Fas-
associated death domain;
Caspase 3, 6, 7
Apoptosis
FADD
Procaspase 8, 10
Caspase 9
Caspase 8, 10
t-BID
Mitochondria
Cytochrome c
BID
Members of the Bcl-2-Family regulate intrinsic pathway and extrinsic pathway in Type II-cells
APAF1
BCL2, BCLXL, MCL1
SMAC/DIABLO
IAP
FLIP
BAX, BAK
DISC
DR
DL
DRType II-Cells
extrinsic
pathway
intrinsic
pathway
The Bcl-2-Family
BH: Bcl-2 homology domain
Guardians
critical for cell survivalanti-apoptotic functions
Effectors
upon activation Bax/Bak mediate MOMPactivation of effector stages of apoptosis
Sensors
essential for initiation of apoptosis signaling
Bax and Bak form poresin the outer mitochondrial membrane
Bcl2 and Bcl-xL inhibit Bax and Bak
BH3-only proteins influence these processes
The Bcl-2-Family
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified.
APAF1, apoptotic protease activating factor-1; BID, BH3-interacting domain death agonist; DR, death receptor; FADD, Fas-
associated death domain;
Caspase 3, 6, 7
Apoptosis
FADD
extrinsic
pathway
Procaspase 8, 10
Caspase 9
Caspase 8, 10
t-BID
Mitochondria
Cytochrome c
BID
APAF1
BCL2, BCLXL, MCL1
SMAC/DIABLO
IAP
FLIP
BAX, BAK
DISCP
CKI/II
Phosphorylation of Bid inhibits its proteolytic cleavage
Type II-Cells
DR
DL
DR
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified.
APAF1, apoptotic protease activating factor-1; BID, BH3-interacting domain death agonist; DR, death receptor; FADD, Fas-
associated death domain;
Caspase 3, 6, 7
Apoptosis
Pro-apoptotic ligand
FADD
DR5
DR4
extrinsic
pathway
Procaspase 8, 10
Caspase 9
Caspase 8, 10
t-BID
Mitochondria
Cytochrome c
BID
IAPs inhibit caspases, inactivated by SMAC
APAF1
BCL2, BCLXL, MCL1
SMAC/DIABLO
IAP
FLIP
BAX, BAK
DISCP
CKI/II
intrinsic
pathway
IAP-Family
IAP: Inhibitors of Apoptosis; BIR: Baculoviral IAP Repeat; CARD: Caspase Activation and Recruitment Domain;
RING: RING zing finger; NOD: Nucleotide-binding Oligomerization Domain; LRR: Leucine Rich Repeat
Model for XIAP-mediated regulation of apoptosis
Healthy cells or cell that
were subjected to sub-lethal
apoptotic stimulus
XIAP binds and inhibits
caspases
Auto-ubiquitination of XIAP
Ubiquitination of caspases
Proteasomal degradation
Cells which were subjected to lethal
apoptotic stimulus
SMAC and Omi released from
mitochondria bind and inhibit
XIAP (and other IAPs)
Auto-ubiquitination of XIAP
Ubiquitination of SMAC/Omi
Proteasomal degradation
of the complex
Massive activation
of free caspases
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
Apoptosis – a tightly controlled cell death programimportant for tissue homeostasis
TRAIL
Caspase 3, 6, 7
Apoptosis
FADD
Procaspase 8, 10
Caspase 9
Caspase 8, 10
t-BID
Mitochondria
Cytochrome c
BID
APAF1
BCL2, BCLXL, MCL1
SMAC/DIABLO
IAP
FLIP
BAX, BAK
DISC
Decoy-Receptors
TRAIL-R1
TRAIL-R2
Immune survaillance
Cellular Stress
Growth factor deprivation
DNA damage
Resistance to apoptosis is a hallmark of cancer
Wong, J. Exp. Clin. Cancer Res. 2011;30:87.
Resistance to apoptosis is a hallmark of cancer
Induction of apoptosisis the aim of many anti-tumor therapies
Wong, J. Exp. Clin. Cancer Res. 2011;30:87.
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified
Apoptosis in anti-tumor therapy – two main strategies
Caspase 3, 6, 7
Apoptosis
death receptor ligand TRAIL
or agonistic antibodies
FADD
Targeting
extrinsic
pathway
Procaspase 8, 10
Caspase 9
Caspase 8, 10
p53
BAX, BAK
Mitochondria
PUMA, NOXA
APAF1
Cytochrome c
DNA damage
BID
t-BID
TRAIL-R1
TRAIL-R2 Chemotherapy
Radiotherapy
p53p53
DNA damage
Targeting
intrinsic
pathway
Targeting the intrinsic apoptosis pathway
Caspase 3, 6, 7
Apoptosis
FADD
Procaspase 8, 10
Caspase 9
Caspase 8, 10
p53
BAX, BAK
Mitochondria
PUMA, NOXA
APAF1
Cytochrome c
DNA damage
BID
t-BID
TRAIL-R1
TRAIL-R2 Chemotherapy
Radiotherapy
p53p53
DNA damage
Targeting
intrinsic
pathway
IAP
BCL2, BCLXL, MCL1
Cancer: Disrupted balance of Bcl-2 family of proteins, overexpression of IAPs,
mutated or non-functional p53
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified.
X
X
Caspase 3, 6, 7
Apoptosis
FADD
Procaspase 8, 10
Caspase 9
Caspase 8, 10
p53
BAX, BAK
Mitochondria
PUMA, NOXA
APAF1
Cytochrome c
DNA damage
BID
t-BID
TRAIL-R1
TRAIL-R2 Chemotherapy
Radiotherapy
p53p53
DNA damage
Targeting
intrinsic
pathway
IAP
BH3 mimetics
SMAC mimetics
BCL2, BCLXL, MCL1
SMAC/DIABLO
Targeting the intrinsic apoptosis pathway
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified.
Restoring the wt
conformation
Inhibition of MDM2-p53
Caspase 3, 6, 7
Apoptosis
FADD
Procaspase 8, 10
Caspase 9
Caspase 8, 10
p53
BAX, BAK
Mitochondria
PUMA, NOXA
APAF1
Cytochrome c
DNA damage
BID
t-BID
TRAIL-R1
TRAIL-R2
Ashkenazi A. Nat Rev Cancer 2002;2:420–430, modified.
Targeting the extrinsic apoptosis pathway
death receptor ligand TRAIL
or agonistic antibodiesextrinsic
pathway
X
TRAIL induces death preferentially in tumor cells (clinical trials), p53 independent!
Tumor cells develop multiple, parallel operatingapoptosis-inhibiting strategies
The misused Death Receptors
Constitutive apoptosis-resistance mechanisms in PDAC cells
BclxL
TRAF2
FLIP
XIAP
c-IAP1/2
Hinz et al., Oncogene 2000
Trauzold et al., Oncogene 2001
Trauzold et al., Br. J. Cancer 2003
Trauzold et al., Faseb J. 2005
Antibody
ApoptosisTRAIL-R1/R2
TRAIL
TRAIL induces death preferentially
in tumor cells (clinical trials)
BH3 mimetics
SMAC mimetics
Trauzold et al., Oncogene 2006
Exogenous TRAIL induces metastasis
(via TRAIL-R1)
Endogenous TRAIL induces metastasis
(via TRAIL-R2) in KRAS-mutated cells
von Karstedt et al., Cancer Cell 2015
Trauzold et al., Oncogene 2001
Siegmund et al., Cell Signal 2007
Lemke et al., J Mol Med 2010
Ehrenschwender et al., Cell Death Diff 2010
Invasion instead of Apoptosis - new Function of death receptors in PDAC (and many other) tumor cells
+ sensitizing agents
+ inhibitors
Current TRAIL-based anti-tumor therapy
•Enhancement of cell sensitivity
•Inhibition of non-apoptotic signaling
•Inhibition of TRAIL?
Apoptosis
Proliferation
Inflammation
Migration/Invasion
Metastasis
Bcl-xL
IAPs
FLIP
Tumor cell
TRAIL-R1/R2
TRAIL
Antibody
High intracellular levels of TRAIL-Receptors correlate with poor prognosis
• Tumor cells express TRAIL receptors mainly in intracellular locations
• high intracellular levels of TRAIL-R2 correlate with poor prognosis
TRAIL-R1 TRAIL-R2
Haselmann et al, … Hauser, Egberts,…..& Trauzold: Gastroenterology, 2014
Bertsch,…, Trauzold; Cell Death & Disease, 2014
nuclear TRAIL-R2 has an oncogenic function
Haselmann et al., Gastroenterology 2014
Tumor cells express TRAIL-Rs mainly intracellularly
Nuclear TRAIL-R2 enhances tumor growth and metastasis
Breast cancer bone-metastasis model
Fritsche et al., Oncotarget 2015
Orthotopic PDAC xenotransplantation model in mouse
Haselmann et al., & Trauzold, Gastroenterology 2014
KD of TRAIL-R2 : HMGA2 myc CXCR4 E-cadherin
Future TRAIL-R-based anti-tumor therapy
Plasma membrane TRAIL Receptors
• enhancement
• sensitisation
• inhibition of non-apoptotic signaling
or
• inhibition of TRAIL-R
• neutralisation of endogenous TRAIL
nuclear TRAIL-R2
• inhibition of the nuclear import
• enhancement of the export
• inhibition of the nuclear functions
Tumor cell
TRAIL-R1/R2
TRAIL
Antikörper
Cell death
Hanahan & Weinberg, 2011, Cell 144: 646-674
Efficient induction and successful execution of cell deathis the aim of many anti-tumor therapies
The paradox of cell death-driven cancer
Labi & Erlacher, Cell Death and Disease (2015) 6, e1675; doi:10.1038/cddis.2015.20
Pro-oncogenic effects of apoptotic cell death
Ichim & Tait, Nature Review Cancer (2016) 16: 539-548.
iPLA2 – calcium-independent phospholipase A2; COX – Cyclooxygenase
„eat me and find me“ signals FKN – fractalkine, ATP, LTF lactotrasferrin
Dying cells affect their surrounding environment in various, yet not fully understood, ways
Stimulate angiogenesis
tumor cell motility
dissemination
Current strategies: Enhancing apoptosiswhile minimizing damage
Ichim & Tait, Nature Review Cancer (2016) 16: 539-548.
CSF1 – Colony stimulating factor 1 receptor, main trophic support factor for macrophages
cell death and cancer
Besides apoptosis, other forms of cell death similarly affect cancer in multifaceted manner
(necrotic cell death – inflammation – tumor promoting and inhibiting effects)
„Improved understanding of the role of cell death in cancer will enable us
to fully harness ist potential as a therapeutic target“
Ichim & Tait, Nature Review Cancer (2016) 16: 539-548.
Exam questions examples: multiple choice
Which answer regarding so called Type II cells is correct?
a) Apoptosis is independent of caspase-8.
b) Apoptosis is independent of mitochondria.
c) Cell death can be inhibited by the overexpression of Bcl-xL.
d) Cytochrome c activates caspase-8 in the DISC.
e) Apoptosis can be inhibited by the overexpression of Bax.
Exam questions examples: free text
1. Please name the cellular organelles, which can act as initiators of the
intrinsic apoptotic cell death (2 Points). Please provide at least one example
per organelle of such organelle-specific death-triggering event (2 Points).
2. Please draw the scheme of TRAIL-mediated apoptotic cell death pathway
in Type I cells (2 Points). Name at least 4 possible anti-apoptotic
mechanisms (2 Points).
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