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Oncoscience > Terms and Molecules > Flashcards

Terms and Molecules Flashcards

1
Q

Type I ovarian cancer

A

25%, Low-grade
Not spreading
Contained to ovaries
Early diagnosis
Mostly Ras, BRAF, PTEN, and beta-catenin mutations

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2
Q

Type II ovarian cancer

A

75%, high grade
Highest prevalence and lethality (HGS)
Late diagnosis, rapid, metastatic
P53, operative cytoreduction!

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3
Q

P63

A

Essential in ectoderm development

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4
Q

P73

A

Delta Np73 inhibitor of usual p53 fanily function
Anti-apoototic
Important in brain development

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5
Q

STIC

A

Serous tubular intraepithelial cancer
Stage (in situ carcinoma) of ovarrian cancer

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6
Q

CA125

A

Tissue marker of peritoneum
Elevated in ovarian carcinoma, pregnancy, cirrhosis, ascites, …

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7
Q

Rituximab

A

mAb against CD20
On pre and mature B cells
B Lymphomas (NHL)

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8
Q

Fc and Fab region

A

Regions of antibodys
Fc region interacts with immune system and induces cell lysis
Fab region binds a specific surfaxe marker (e.g. Rituximab binds CD20)

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9
Q

FISH

A

flourescence in situ hybridization
Flourescent DNA or RNA probes hybridize
Detection of translocations and copy number variations

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10
Q

Her2

A

Amplification associated with poor prognosis and increased recurrence in breast cancer
Maybe involved in tumorigenesis and therapy resistance to some chemotherapies
Diagnosis importent for therapeutic descicions

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11
Q

Causes of genetic instability

A

Environmental (lifestyle: smoking, diet and UV and IR exposure, viral/bacterial infections, …)
Genetics: defects in DDR, cellcycle regulation, checkpoints, …

In total causes high mutation rate or chromosomal instability

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12
Q

G1 checkpoint

A

CDK4/6
Cyclin D

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13
Q

G1/S checkpoint

A

CDK 2
Cyclin E

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14
Q

S checkpoint

A

CDK 2
Cyclin A

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15
Q

G2 checkpoint

A

CDK 1
Cyclin A

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16
Q

M checkpoint

A

CDK 1
Cyclin B

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17
Q

Checkpoints definition

A

Monitor and control the completion and irder of major cell cycle events

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18
Q

Types of DNA damage

A

Loss of bases
Modification of bases
Strand breaks
Blocked DNA replication

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19
Q

Intertumor heterogeneity

A

Tumors of different patients have different genetic profiles even when stemming from the same tissue or cell type since mutations occur randomly and even driver mutations can vary

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20
Q

Intratumor heterogeneity

A

Higher mutations rates allow development of driver mutations within one cell and subsequent tumorigenesis
During this process and after many other mutations occur from which some may have replicative benefits, different cells may develop different mutations with reolicative benefits which lads to their increased expansion –> subclones

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21
Q

Initiator caspases

A

8 (extrinsic)
9 (intrinsic)
10

Activated through dimerization and autoprocessing through adaptors

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22
Q

Executioner caspases

A

3, 6 and 7
Activation through clevage by initiator caspases

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23
Q

Caspase activation

A

Executioner through clevage by initiator
Initiator through dimerization through adaptors

Adaptors through apoptosis-inducing signals
–> LOSS of MITOCHONDRIAL INTEGRITY
–> RECEPTOR-LIGAND interaction
–> CELL-CELL CONTACT

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24
Q

Bcl2 family type & role in MOMP
BAX/BAK

A

pro-apoptotic multidomain
dimerize and release cytochrome c
usually inhibited through anti-apoptotic Bcl2 (Bcl-2, Bcl-XL, …)

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25
Q

Bcl2 family type & role in MOMP
Bcl-2 (Bcl-XL, Mcl-1)

A

anti-apoptotic
bind Bax/Bak and prevent dimerization
inhibited by BH3 only –> apoptosis

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26
Q

Bcl2 family type & role in MOMP
BIM

A

pro-apoptotic BH3 only
bind anti-apoptotic Bcl-2 and desinhibit Bax/Bak dimerization

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27
Q

Bcl2 family type & role in MOMP
BID

A

pro-apoptotic BH3 only
bind anti-apoptotic Bcl-2 and desinhibit Bax/Bak dimerization

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28
Q

Bcl2 family type & role in MOMP
BAD

A

pro-apoptotic BH3 only
bind anti-apoptotic Bcl-2 and desinhibit Bax/Bak dimerization

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29
Q

Complex I formation
TNF-receptor ligation

A

Caspase-8 and c-FLIP-L
NFkB signaling, JNK and p38
SURVIVAL

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30
Q

Complex II formation
TNF-receptor ligation

A

Caspase-8 and Caspase-8
activation of Caspase 3 and BID
APOPTOSIS

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31
Q

Complex III formation
TNF-receptor ligation

A

Caspase-8 and v-FLIP or c-FLIP-S
NECROPTOSIS

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32
Q

Cell death pathways as target for anti-cancer therapy

A

BH3-mimetics (= Bcl2 inhibitors)
XIAP inhibitors = Smac mimetics
RTKi target BIM, BAD, BMF

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33
Q

Biogenesis of miRNA

A

Transcription of pri-miRNA
Processing through DROSHA/PASHA to pre-miRNA
Nuclear export (Exportin 5)
Dicing through TRBP/Dicer-1 to miRNA:miRNA* duplex
RISC loading from pre-RISC to mature RISC

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34
Q

DROSHA/PASHA

A

processing pri-miRNA to pre-miRNA within the nucleus

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35
Q

Exportin-5

A

nuclear export of pre-miRNA into the cytosol

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36
Q

TRBP

A

in complex with Dicer-1 dicing of pre-miRNA to miRNA:miRNA* duplex

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37
Q

Dicer-1

A

in complex with TRBP dicing of pre-miRNA to miRNA:miRNA* duplex

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38
Q

TRBP/Dicer-1

A

dicing of pre-miRNA to miRNA:miRNA* duplex

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39
Q

global miRNA reduction
example for reason
consequnces

A

e.g. through Exportin-5 defect
promotes tumorigenesis

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40
Q

oncomiRNA
examples and consequences

A

overexpression promotes tumorigenesis (e.g. miR-17-92 inhibits PTEN)
can also induce EMT (e.g. miR-21 is induced through androgens, causes EMT and inhibits pro-apoptotic protein PDCD4)

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41
Q

miR-17-92

A

oncomiRNA
inhibits PTEN

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42
Q

onco-miRNAs

A

miR-17-92: inhibits PTEN
miR-21: induces EMT and inhibits PDCD4 (pro-apoptotic), regulated via androgens

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43
Q

miRNA seed region

A

nts 2-6
require perfect base pairing –> determine selectivity of targets

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44
Q

lncRNAs in gene regulation
mechanisms

A

guides
decoys
scaffolds
enhancers

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45
Q

ceRNA

A

competing endogenous RNA
coregulation with mRNA transcript through identical RISC-binding sites

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46
Q

Ras activation and consequence

A

inactive GDP-bound Ras activated through GEF that exchanges GDP with GTP
shift in swith regions I and II
enables interaction with effectors containing RBD

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47
Q

MAPK cascade with examples

A

small G protein (Ras)
MAPKKK (BRAF)
MAPKK (MEK)
MAPK (ERK1/2)
effector

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48
Q

Markers of EMT (up and down)

A

E-cad down
N-cad up
MET up
HGF up
HDGF up
Oct4 and BIM-1 up

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49
Q

TF regulating EMT

A

Snail & Twist (induced by TGF-beta)

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50
Q

tumor suppressive miRNAs

A

miR-29b: inhibits metastasis, E-cad up, N-cad down, Snail&Twist down
miR-338-5p & miR-421: reduce EMT markers and stemness, proliferation, growth and metestasis

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51
Q

regulation of EMT through steroid hormones

A

onco-miR-21 redgulated through androgens
promotes EMT and inhibits PDCD4 (anti-apoptotic)

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52
Q

experimental therapies to target EMT

A

ZOLEDRONIC ACID: reverses EMT, Snail&Twist, N-cad, Oct4 and BIM-1 down

SD-208: reverses TGF-beta induced EMT, BRachyury, migration and invasion down, chemosensitivity up

PROTEOSOME INHIBITOR: reduces Snail

Wnt INHIBITORS: reduce EMT

targeting EGF, EGFR, and ErbB2 –> reduces EMT

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53
Q

TGF-beta and EMT

A

causes growth, immunosuppression, angiogenesis and EMT
E-cad down, Fibronectin and Twist&Snail up
induces TF Brachyury –> increases invasiveness

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54
Q

Heat shock proteins and EMT

A

Hsp27 induces EMT
chaperone of oncogenes
E-cad down
Wnt, mesenchymal proteins and MMP up
Hsp27 essential for IL6 and therefore the IL6/STAT/Twist pathway

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55
Q

Zoledronic acid

A

experimental therapy to target EMT
reverses EMT
Snail&Twist, N-cad, Oct4 and BIM-1 down

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56
Q

SD-208

A

experimental therapy to target EMT
reverses TGF-beta induced EMT
Brachyury, migration and invasion down
chemosensitivity up

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57
Q

Proteosome inhibitors

A

experimental therapy to target EMT
reduce Snail

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58
Q

Wnt inhibitors

A

experimental therapy to target EMT
reduces EMT

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59
Q

target EGF, EGFR and ErbB2

A

experimental therapy to target EMT
reduces EMT

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60
Q

Hsp27

A

heat shock protein
chaperone to oncogenes
induces EMT (E-cad down
Wnt, mesenchymal proteins and MMP up)
essential for IL6 and therefore the IL6/STAT/Twist pathway

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61
Q

lymphatic spread

A

PERMEATION: easy access through lack of thight junctions, BM and astrocytes –> intravasation for hematogenous spread requires proteolytic enzymes
CHEMOTACTIC DIFFUSION: cytokines of lymphatic vessels promote infiltration
LYMPHANGIOGENESIS: tumor cell induced vessel formation (VEGF-C)

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62
Q

MMPs
function

A

remodelling of ECM components through degradation and clevage
Znc-dependend endopeptidases, activated through clevage by proteinases

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63
Q

MMPs
structure

A

membrane-bound and secreted MMPs (can interact with cytoskeleton)
metal ion at center (often Znc)
PRO-PEPTIDE: autoinhibition, activation requires its clevage
CATALYTIC DOMAIN: active site, contains Znc2+
C-TERMINUS: protein-protein interactions, e.g. TIMPs

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64
Q

challenges for CTCs

A

shear forces –> mechanical destruction
immunological clearance

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65
Q

survival mechanisms of CTCs

A

dynamic regulation of cellular stiffness and contractility
close interaction with blood microenvironment
clusters of CTCs show better survival as single cells

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66
Q

seed & soil hypothesis

A

Stephan Paget
metastasis formation reuqires the right cell to be in the right environment
for certein tissues of origin certain organs are beneficial (but it also depends on the individual genetics of the cell in question)

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67
Q

anatomical hypothesis

A

metastasis depends on the blood flow downstream of the primary tumor
CTCs form metastasis in small vessels downstream –> liver or lung
for splanchnic organs = liver, rest = lung

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68
Q

definition CTCs

A

cells that successfully detached form their primary tumor and intravasated (& survived in the blood)

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69
Q

detection of CTCs

A

hard, low cell number esp. when comparing to blood cells
MACS: density, CD45 and EpCAM
CellSearch: EpCAM
ScreenCell Filtration: size
ParsortixTM microfluidic system: deformability and size

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70
Q

CTC detection - MACS

A

depending on density, CD45 and EpCAM

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71
Q

CTC detection - CellSearch

A

depending on EpCAM (often loss during EMT!)

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72
Q

CTC detection - ScreenCell filtration

A

depending on size

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73
Q

CTC detection - ParsortixTM microfluidic system

A

depending on size and deformability

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74
Q

reasons for metabolism alterations in tumors

A

sustaining proliferative signaling
enabling replicative immortality
evading cell death
evading growth suppressors
activating invasiveness and metestasis
inducing angiogenesis

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75
Q

tumor-specific metabolic adaptations

A

TCA cycle
lipolysis, proteolysis, glutaminolysis
lipogenesis
redox status
glycolysis –> Warburg and Carbtree effect

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76
Q

Benefits of Glycolysis

A

indipendent form fluctuations in oxygen tension
generating bicarbonic and lactic acid –> acidification and increased invasiveness
PPP generates NADPH –> antioxidant
intermediates used for macromolecular biogenesis

77
Q

causes for metabolic adaptations

A

environment: hypoxia induces HIF –> expression of glycolytic enzymes
cancer genes themselves
tumor specific isoforms: M2 of PK (catalyzes rate limiting step)
Mutations: e.g. IDH (D-2HG)

78
Q

therapies targeting metabolism

A

targeting METABOLIC ENZYMES of CARBON metabolism (e.g. LDH, IDH, PDK)
targeting LIPOLYSIS, GLYCOLYSIS, TCA (mitochondrial metabolism)
AEROBIC GLYCOLYSIS INHIBITORS

79
Q

detection of alterations in ROS levels

A

reagents that change colour or flourescent emission upon oxidation –> flourescence microscopy or FACS

80
Q

detection of changes in mitochondrial morphology

A

microscopy (confocal imaging)
mayby mitochondrial staining

81
Q

inductors of switch to glycolysis

A

hexokinase
PI3K/Akt
Myc and MondoA
HIF
p53

82
Q

Pro and cons of ROS

A

oxidation of proteins
regulate protein stability
increase/decrease function (constitutive EGFR activation)
alter subcellular localization (translocation)
altered prot-prot interaction

low levels physiological, intermediate is tumorigenic through adaptive proteins and mutagenesis), high levels is cytotoxic

83
Q

Carbtree effect

A

increased glucose levels and uptake do not increase oxygen tension instead oxygen uptake is reduced in presence of glucose
this can be found in tumor cells and other rapidly dividing cells (thymocytes, spermatozoae, mucosal cells, ESCs)

84
Q

Warburg effect

A

switch from oxidative phosphorylation to aerobic glycolysis
dependend on glucose

85
Q

Warbur effect
advantages

A

switch from oxidative phosphorylation to aerobic glycolysis

less dependency on oxygen
ACIDIFICATION of tumor environment –> immune evasion and DDR inactivation (mutagenesis)
INVASIVENESS and METASTASIS –> elevated MMP, lactate increases HYALURONAN (single cells) and CD44 (motility)

86
Q

HIF1-alpha stabilization

A

induces glycolytic enzymes
degraded by Von Hippel Lindau (VHL, E3 ubiquitin ligase)

VHL MUTATIONS
ONCOGENE SIGNALING (Ras, Src, PKB, …)
TCA CYCLE ENZYMES
ROS (stabalizes HIF)

87
Q

HIF1-alpha

A

inductor of switch to glycolysis
induces glycolytic enzymes
degraded by Von Hippel Lindau (VHL, E3 ubiquitin ligase)

88
Q

Hexokinase II

A

inductor of switch to glycolysis
anti-apoptotic properties
catalyzes the rate-limiting step during glycolysis
regulated by Myc (elevated –> elevated)

89
Q

PI3K/Akt

A

inductor of switch to glycolysis

90
Q

Myc

A

with MondoA inductor to switch to glycolysis

in combination with MAX: increase of glycolytic enzymes
- Hexokinase II
- GAPDH
- Enolase-1
- Pyruvate kinase
- Lactate dehydrogenase

91
Q

p53

A

inductor of switch to glycolysis
loss increases glycolysis
TIGAR: induced by p53, reduces glycolysis
SCO2: induced by p53, necessary for COX complex assembly (important for respiratory chain)
PGM: repressed by p53, catalyzes step in glycolysis

92
Q

drug-unspecific resistance mechanisms

A

drug efflux
cell death inhibition
EMT
epigenetics

93
Q

drug-specific resistance mechanisms

A

drug metabolism –> inhibition or prohibition of activation
mutations in drug target
DDR
activation of alternative signaling pathways

94
Q

therapeutic strategies to reduce expression of MDR protein transporters

A

polypeptide transcriptional repressor
siRNAs
ribozyms
glycosylation inhibitor (important for folding)

95
Q

extrinsic cell death inhibition

A

loss of caspase 8
increased expression of FLIP (caspase 8 inhibitory protein)
overexpression of IAPs

96
Q

DNA methylation in cancer and therapy resistance

A

hypomethylation of oncogenes (e.g. proliferative proteins)
hypermethylation of tumorsuppressors (e.g. pro-apoptotic proteins)

DRUG RESISTANCE: changes in methylation pattern for better DDR, drug efflux, changes in drug metabolism, EMT, …
example: hypomethylation of UGT1A1 –> resistance to irinotecans active metabolite SN38

preventing hypermethylation of anti-tumor sequences through cytidine-analogs that cannot be methlyated

97
Q

evasion of cell death by DNA damaging drugs

A

drug efflux
cell death inhibition
increased DDR
epigenetics
drug inactivation/metabolisation

98
Q

lactate in tumor survival and metastasis

A

increases HYALURONAN –> less adhesion, more single cells
increases CD44 –> cytoskelletal interaction -> motility
acidification of tumor environment –> immune evasion and mutagenic (nactivation of DDR)

99
Q

glycolysis inhibitors

A

2-deoxyglucose
3-bromopyruvate
DCA (dichloroacetat)
siRNAs inhibiting LDH (lactate dehydrogenase)
Somatostatin and derivate TT-232

100
Q

2-deoxyglucose

A

glycolysis inhibitor

101
Q

3-bromopyruvate

A

glycolysis inhibitor

102
Q

DCA (dichloroacetat)

A

glycolysis inhibitor

103
Q

Somatostatin

A

glycolysis inhibitor
derivate is TT-232

104
Q

TT-232

A

derivate of Somatostatin
glycolysis inhibitor

105
Q

inhibition of LDH

A

with siRNAs
inhibition of glycolysis

106
Q

donor of methyl groups

A

methionine
mostly as SAM (S-adenosylmethionine) = Methionine + ATP

107
Q

metabolic cycling of methionine

A

uptake through diet
+ ATP –> SAM
SAM = SAH + CH3
SAH (S-adenosylhomocystein) –> Hyc (Homocystein)
Hyc remethylated (Vit. B12 and 5-methyl-THF) to methionine or catabolized (Vit. B6)

108
Q

epigenetically regulated metabolic enzymes

A

CYP1A1: metabolization of PAHs (polycycling aromatic hydrocarbons) to carcinogenic intermediates
UGT1A1: drug resistance to irinotecan by inactivating active metabolite SN38
NAT 1&2: inactivation of carcinogens

109
Q

CYP1A1

A

metabolic enzyme
metabolization of PAHs (polycycling aromatic hydrocarbons) to carcinogenic intermediates
hypomethylated in cancer

110
Q

UGT1A1

A

metabolic enzyme
metabolization of small lipids to excretable water-soluble molecules
drug resistance to irinotecans active metabolite SN38
hypomethylated in cancer

111
Q

Irinotecan

A

cancer therapeutic
active metabolite = SN38
inactivated through metabolization by UGT1A1

112
Q

SN38

A

active metabolite of irinotecan
inactivated by metabolization through UGT1A1

113
Q

NAT2

A

N-acetyltransferase
can inactivate carcinogens by metabolization
hypermethylated in cancer

114
Q

epigenetic effects of D-2HG

A

D-2 hydroxygluterate
oncogenic driver via epigenetic reprogramming in mIDH associated cancers
produced by mIDH1/2

TET2 INHIBITION: leads to CpG hypermethylation
KDMs INHIBITION: leads to histone hypermethylation

promotes BM disruption

115
Q

TET2

A

prevents CpG methylation
inhibited by D-2HG (oncometabolite of mIDH1/2)

116
Q

KDMs

A

lysine demethylases (e.g. JHDM)
prevent histone methylation
inhibited by D-2HG (oncometabolite of mIDH1/2

117
Q

metabolite of mutated IDH1/2

A

D-2HG
D-2 hydroxygluterate
oncogenic driver via pigenetic reprogramming in mIDH1/2 associated cancers

118
Q

SIRT6

A

HDAC (histone deacetylase)
reduces the expression of glycolytic genes
may act as tumorsupressor by preventing switch to aerobic glycolysis
repress Myc transcriptional activity

deficiancy promotes Myc activity and ribosome biogenesis

119
Q

interplay of epigenetics and metabolism in glucose metabolism

A

GlnAc: produced from glucose entering the hexosamine biosynthetic pathway –> GlnAc of histones

Sirtuins: HDACs, regulated through NAD+ levels

TCA intermediates
- Citrate: conversion to Acetyl-CoA –> HAT
- alpha-KG: cofactor for DE-METHYLATION of histones and DNA
- Methionine: donor for HMT and DNMT
- low ATP/AMP ratio: activation of AMPK –> histone phosphorylation

120
Q

GlnAc

A

produced from glucose entering the hexosamine biosynthetic pathway
GlnAcylation of histones

121
Q

Citrate and epigenetics

A

converted to Acetyl-CoA
donor for HAT (histone acetylation)

122
Q

alpha-KG and epigenetics

A

cofactor for DE-METHYLATION of histone and DNA

123
Q

methionine and epienetics

A

donor for HMT and DNMT
mostly as SAM

124
Q

ATP/AMP ratio

A

low ratio activates AMPK
causes histone phosphorylation

125
Q

FRET

A

flourescence resonance energy transfer
energy transferred from a donor flourophore to an acceptor without emission
acceptor emission is changed/induced, …

enzyme assays: e.g. protease inhibitors
protein conformation
protein-protein interaction

126
Q

application of FRET

A

enzyme assays: e.g. protease inhibitors
protein conformation
protein-protein interaction

127
Q

main questions in drug discovery project planning

A

SCIENTIFIC & TECHNICAL: hypothesis, target, assays, animal models
STRATEGIC: unmet medical need, market predictions, …
OPERATIONAL: staff, facilities, cost, timescale

128
Q

HTS

A

high throughput screening
analysis of a large number of compounds in microtiter plates

129
Q

HTS-Assays

A

ENZYMATIC: chromogenic or flourescent substrate
COUPLED ENZYME ASSAY + PROMOTOR: e.g. effect of protein of interest on a promotor inducing luciferase –> measurment of luciferase activity
MEMBRANE PREPARATIONS
PHENOTYPIC ASSAY: e.g. whole living cells and GFP-labeled protein, detection of translocation into the nucleus

130
Q

SPR

A

surface plasmon resonance
measurment of direct molecule-molecule interactions in realtime

polarized light on a gold-film causes them to resonate –> measurment of resonance and reflection
on the gold film a protein/fragment/DNA etc. can be bound, if it interacts with its binding partner then there is a change in mass and therefore resonance and reflection (measured)

presentation in sensogramm (resonance over time) –> association, dissociation ans regeneration

131
Q

ideal drug target

A

no IP or competition
3D structure known or clear active/catalytic domain
disease causing/modifying
analyzation with HTS possible
bimarker to observe effects in organisms

132
Q

whole animal screening

A

C. elegans, D. melanogaster, D. rerio
cultivation of animals in microtiter plates

THERAPEUTICAL SCREEN: reversion to wildtype, control = phenotype
CHEMICAL GENETICS SCREEN: induction of phenotype, control = wildtype

133
Q

therapeutical screen
(whole animal screening)

A

compound should induce a reversion to wildtype
control = phenotype

134
Q

chemical genetics screen
(whole animal screening)

A

compound should induce a phenotype
control = wildtype

135
Q

innate immune cells involved in tumor immunity

A

NK cells
DCs
macrophages (TAM2 pro-tumorigeneic)

136
Q

adaptive immune cells involved in tumor immunity

A

B cells
CD4+ T cells
CD8+ T cells
T regs

137
Q

tumor immune escape mechanisms

A
  • upregulation of immune-inhibitory proteins (CTLA4, PDL-1, PD-1)
  • loss of antigen and MHC-I
  • acidification of tumor environment
  • exclusion of immune cells through ECM modification
  • cytokines and molecules inhibiting DC maturation and differentiation (e.g. IL-6, IL-10, VEGF)
  • chemokines recruiting tumor-promoting immuen cells
138
Q

immunotherapeutical approches

A

TUMOR-Ag VACCINATION: isolation and injection + adjuvant
ADOPTIVE T CELL THERAPY:
- CAR-T cells: selection or transfection
- NK cells: isolate, purify, expand & activate
- DC therapy: load precursors with Ag –> immune response and boost
ANTIBODY THERAPY: desinhibition of T cells (a-CTLA4, a-PD(L)-1)

139
Q

adoptive T cell therapy

A
  • CAR-T cells: selection or transfection
  • NK cells: isolate, purify, expand & activate
  • DC therapy: load precursors with Ag –> immune response and boost
140
Q

tumor-Ag vaccination

A

isolation of Ag
injection i.v. or i.d. with adjuvant

141
Q

antibody therapy

A

e.g. desinhibition of T cells (a-CTLA4, a-PD-1, a-PDL-1)

142
Q

DCs in tumor immunity

A

initiators of anti-tumor immunity
incorporation of tumor cells, degradation, transport and presentation of Ag
in tumors numbers reduced and functionally impaired
impairment promotes tumorigenesis and progression

143
Q

key steps of autophagy

A

initiation
expansion of phagofore an formation of autophagosome
transport to lysosome and fusion
autophagic breakdown and recycling

144
Q

kinase-complex essential for supression of autophagy

A

mTORC1
sensor of AA and GF
if enough is present then inhibition of autophagy by phosphorylation of ULK1-complex

145
Q

kinase-complex essential for autophagy

A

ULK1-complex
consits of ULK1, ATG13 and FIP200
continously phosphorylated and inhibited through mTORC1
mTORC-1 inhibition allows dephosphorylation and activation

146
Q

types of selective autophagy

A

mitophagy
pexophagy
reticulophagy
ribophagy
xenophagy
aggrephagy

147
Q

inductor of bulk autophagy

A

starvation

148
Q

starvation causes …

A

bulk autophagy

149
Q

cell types in stroma

A

edothelial cells
immune cells
smooth muscle cells
fibroblasts
neurons

150
Q

upregulated markers in CAFs (3)

A

FAP
alpha-SMA
S100A4 (= FSP1)
PDGF-receptors
CD90/Thy1
Tenascin C

151
Q

tumor-promotig effects of CAFs

A

DIRECT: secretion of mitogenic factors (paracrine), direct cell-cell-contacts
INDIRECT: modulation of immune cells, alterations of ECM, angiogenesis, metabolic reprogramming

THERAPY RESISTANCE: reduce efficacy of chemotherapy, andocrine/target resistance

152
Q

factors remodelling ECM in tumor-associated stroma

A

IL-1b, Wnt and TGF-beta drive CAF-subsets

Rho-ROCK: modulates cytoskelletal organisation –> collagen-track formation
CAVEOLIN-1: activates Rho-ROCK, elevated stromal Cav-1 correlates with increased metastasis
YAP & TAZ: promote proliferation and motility, translocation to nucleus induced by mechnical stimuli

153
Q

FAP

A

upregulated marker in CAFs

154
Q

alpha-SMA

A

upregulated marker in CAFs

155
Q

FSP1

A

= S100A4
upregulated marker in CAFs

156
Q

S100A4

A

= FSP1
upregulated marker in CAFs

157
Q

PDGF-receptor

A

upregulated in CAFs

158
Q

Rho-ROCK

A

factor remodelling ECM in tumor-associated stroma
modulates cytoskelletal organisation –> collagen-track formation

159
Q

Caveolin-1

A

factor remodelling ECM in tumor-associated stroma
activates Rho-ROCK
elevated stromal Cav-1 correlates with increased metastasis

160
Q

YAP

A

with TAZ
factor remodelling ECM in tumor-associated stroma
promote proliferation and motility, translocation to nucleus induced by mechnical stimuli

161
Q

TAZ

A

with YAP
factor remodelling ECM in tumor-associated stroma
promote proliferation and motility, translocation to nucleus induced by mechnical stimuli

162
Q

immune suppressive mechanisms of tumor-associated ECM

A
  • reduced T cell proliferation (stiff)
  • reduced T cell activation (impaired Ag presentation, activation)
  • limited motility (stiff and dense)
  • TAM2 promoton (collagen-rich and rigid ECM favor polarization to M2 phanotype)
163
Q

infiltrating cell types from which CAF can originate

A

endothelial cells
adipocytes
marrow-derived stromal cells
pericytes
(tumor cells)

164
Q

consequences of increased mechanical tension in tumor-associated microenvironment (3)

A
  • induces fibroblast activation to SMA+ myCAFs
  • activates latent MMPs
  • collagen production elevated
  • local release of ECM-stored GFs (TGF-beta, IGF, HGF)
  • reveals cryptic sites in ECM molecules
  • modified cellulare responses via integrin/FAK association
165
Q

consequences of increased mechanical tension in tumor-associated microenvironment (3)

A
  • induces fibroblast activation to SMA+ myCAFs
  • activates latent MMPs
  • collagen production elevated
  • local release of ECM-stored GFs (TGF-beta, IGF, HGF)
  • reveals cryptic sites in ECM molecules
  • modified cellulare responses via integrin/FAK association
166
Q

CAF regulating tumor immune response

A

RECRUITMENT OF INNATE & ADAPTIVE IMMUNE CELLS: e.g. via CXCL12 for macrophages or CCL2 for monocytes

MODULATE THEIR ACTIVITY:
- FAP+ CAFs are immuno suppressive
- TGF-beta: released by CAFs, reduces T, NK and CD8+ cells, increases recruitment of tumor-promoting cells
- TSLP: secreted, polarizes T cells to Th2 immunity (tumor- promoting)

167
Q

TGF-beta

A

RELEASED BY ECM AND CAFs:
reduces numbers of T cells, NK cells and CD8+ T cells
increses recruitment of tumor-promoting immune cells

IN EMT:
causes growth, immunosuppression, angiogenesis and EMT
E-cad down, Fibronectin and Twist&Snail up
induces TF Brachyury –> increases invasiveness

168
Q

safety features of oncolytic viruses

A

non-human pathogenic viruses
dependency of replication on tumor-associated features (active cell cycle, signaling pahways, deficiency of IFN or p53)

169
Q

safety concerns of oncolytic viruses

A

specifity for tumor tissue
cytokine storm (virus progeny!)

170
Q

tumor targeting mechanisms of oncolytic viruses

A

EXTRACELLULAR: inf. of tumor vasculature, increased potency through tumor-associated e.g. proteases in ECM
CELL SURFACE: natural tropism or engineered retargeting towards tumor-associated markers or neoantigens
CYTOSOLIC: dependency on oncogenic signaling apthways (Ras, EGFR), dependency on IFN deficiency
NUCLEAR: active cell cycle, p53 deficiency, active RB pathway

171
Q

extracellular tumor targeting mechanisms of oncolytic viruses

A

infection of tumor vasculature
increased potency through e.g. tumor-associated proteases in ECM

172
Q

cell surface tumor targeting mechanisms of oncolytic viruses

A

natura tropism or engineered retargeting towards tumor-associated surface markers or neoantigens

173
Q

cytosolic tumor targeting mechanisms of oncolytic viruses

A

dependency on oncogenic signaling pathways (EGFR, Ras)
dependency on IFN deficiency

174
Q

nuclear tumor targeting mechanisms of oncolytic viruses

A

dependency on active cell cycle
dependency on deficient p53
dependency on RB pathway

175
Q

heterologous cancer vaccines

A

prime & boost principle
combination of oncolytic virus with non-oncolytic vaccine
oncolytic virus induces anti-viral and anti-tumor response, release of neoantigens
vaccine boosts the existing anti-tumor response selectively
transient oncolytic effect and long-lasting, more robust and more effective anti-tumor response

176
Q

challenges of oncolytic-viruses-based therapy

A

granting tumor specifity and no infection of helathy cells
generating anti-tumor and not only anti-viral responses
overactivation of immune system (cytokine storm)
changes in ECM prevent viral infiltration
pre-existing immunity to virus (e.g. adenovirus)

177
Q

structural element of the protein kinase domain

A

N-lobe
C-lobe
activtation loop
catalytic cleft

178
Q

classification of protein kinases

A

Serin/threonin kinases
Tyrosin kinases

179
Q

role of protein kinases in regulating protein function

A

SIGNAL RECEPTION/TRANSDUCTION: receptors have PK activity or are associated with PK

ACTIVITY: conformational shifts through phosphorylation can change activity status, reveal binding sites

INTERACTION: phosphorylation itself as binding partner (SH domains)

FUNCTION: posttranslational modifications for correct function

180
Q

regulation of substrate recognition in protein kinases

A

physical interactions

CATALYTIC CLEFT: accomodates site of phosphorylation and several neighbouring AA –> dependend on size and charge
DOCKING SITE & DOMAIN INTERACTIONS: increase specifity and affinity, can induce conformational shifts (activation)
ADAPTORS & SCAFFOLDS: increase proximity and speed, can cause conformational shifts to promote phosphorylation

181
Q

structure of intracellular signaling pathways

A

signal
reception
processing
output

182
Q

signal propagation

A

a defined cascade of protein/factor activation and inactivation
elevated/accelerated through scaffolds
additional regulation, inhibition or increase through feedback loops

183
Q

role of UPR in tumorigenesis

A

involved in nearly all hallmarks of cancer
- evading growth supressors, cell death and immune destruction
- inducing tumor promotig inflammation, angiogenesis, invasion and metastasis, genome instability and mutagenesis
- sustainming prolifertive signaling
- deregulation of cellular energetics

184
Q

examples/pathways of UPR in tumorigenesis

A

inflammation, mutagenesis, stemness, growth and angiogenesis

ER stress in macrophages –> PERK, IRE1, ATF6 –> cytokines –> inflammation –> elevated ROS –> mutagenesis

ER stress –> IRE1 –> XBP1s –> increased stemness and tumor growth

ER-stress –> PERK –> ATF4 –> VEGF –> angiogenesis

185
Q

elevated XBP1s in tumors

A

increases stemness and tumor growth

186
Q

ATF4 in tumors

A

VEGF release –> angiogenesis

187
Q

ER stress in macrophages

A

induction of PERK, ATF6 and IRE1
cytokine production
inflammation
elevated ROS
muatgenesis

188
Q

sensors of ER stress + TF

A

PERK –> ATF4
IRE1 –> XBP1s
ATF6 –> intracellular fragment (ATF6p50)

189
Q

enzymatic domains in IRE1 and function

A

KINASE domain –> trans-autophosphorylation upon oligomerization

ENDONUCLEASE domain –> splicing of one intron in XPB1 –> active TF XBP1s

Oncoscience (2 decks)

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