Pathology - Cancer Flashcards
1
Q
what is the default pathway for a single cell and what does it need to counter this
A
apoptosis
cell-cell signaling and growth factors
2
Q
what is apoptotic blebbing
A
in an apoptotic cell the light is fragmented unevenly compared to a non-apoptotic spherical cell
3
Q
what does apoptotic blebbing lead to
A
pykonisis
4
Q
what is DNA damage detected by
A
p53
5
Q
what does p53 activate when it detects DNA damage
A
Bax
6
Q
function of Bax
A
creates holes in the mitochondria - releases signaling molecules
7
Q
what to the signaling molecules in from mitochondria activate
A
Caspase 9
8
Q
function of Caspase 9
A
cleaves an activates Caspase 3/6/7
9
Q
what is the function of cleaved Caspase 6/3/7
A
cleaves I from CAD in ICAD - leads to active conformation CAD
10
Q
function of CAD
A
DNA fragmentation
protein cleavage
nuclear membrane loss
organelle breakdown
11
Q
what are is the sequence that leads to Caspase 8 activation
A
Extrinsic stimuli
Death cell receptor
12
Q
what does Caspase 8 activate specific to Type I extrinsic pathway
A
tBid
13
Q
function of tBid
A
releases mitochondrial contents - act as signaling molecules
14
Q
what does Caspase 8 cleave which is common in all apoptotic processes
A
Caspase 6/3/7
15
Q
what happens when effector caspases are activated
A
substrate cleavage
further initiator caspase activation
16
Q
what are the initiator caspases
A
Caspase 9/8 and also 10 (rare)
17
Q
what are the effector Caspases
A
Caspase 3/6/7
18
Q
what is DISC
A
multi-protein complex responsible for caspase 8 activation via the extrinsic pathway
19
Q
what happens when cytochrome c is released into the cytoplasm
A
binds to APAF-1
20
Q
what does the binding of APAF-1 and cytochrome c lead to
A
an apoptosome - wheel of death
21
Q
what binds to the apoptosome
A
Caspase 8
22
Q
what is the structure of a BH3 domain
A
a group of Bak/Bax proteins that form a tunnel in the mitochondrial membrane
23
Q
function of the BH3 domain
A
makes a pore in the mitochondrial membrane to release its contents
24
Q
how is Bim de-activated
A
degraded by a proteosome
25
how is Bmf imobillised
sequestrated by the cytoskeleton - binds via DLC-2
26
how is Bad inactivated
many growth factors phosphorylate Bad
27
what is targeted therapy to promote apoptosis
target Bcl-2 with a BH3 mimetic to bind to Bcl-2
28
how is glucose uptake affected in breast cancer cells
invasive cells have increased glycolysis compared to hypoxia-induced decrease in glycolysis in non-invasive cells
29
what is the hypoxia-mediated selection hypothesis
increased aerobic glycolysis makes the tumour cells more likely to survive periods of low oxygen
30
what is the reversible regulation of glycolysis regulated by
PFK1-phosphofructokinase - its the rate-limiting enzyme in glycolysis
31
what is PFK1 activated and inhibited by
inhibited by ATP
activated by AMP
32
what are the function of PHD's
they are oxygen-dependent prolyl hydroxylases that hydroxylate HIF1alpha
33
what happens once HIF1alpha is hydroxylated
pVHL is recruited to HIF1aplha
this targets HIF1aplha for proteome-dependent degradation
34
what is HIF1alpha
a transcription factor for expression of glycolysis and autophagy (cell eating itself) when no oxygen
35
do you get how oxygen presence leads to decreased glycolysis and autophagy
yes
36
how dos oxygen depletion effect PFK1 expression
increase in HIF1alpha leads to increase in PFK1to increase glycolysis
37
what is irreversible regulation of glycolysis
mutation in fumarate hydratase (FH) and succinate dehydrogenase (SDH)
38
how do mutations in FH and SDH cause cancer
they inhibit PDH's which increase HIF1alpha expression which leads to increased glycolysis and other hallmarks of cancer
39
what are the functions of metalloproteinases (MMP's) in metastasis
break down extracellular membrane and cell adhesion molecules
40
difference between secreted and transmembrane MMT's
secreted - are used to degrade nearby cells
transmembrane - are used for the invasion of the tumour cell
41
what are the first 3 steps of invasion-metastasis cascade
1 - breaking down basal membrane
2 - EMT and intravasation
3 - anoikis resistance
42
what are steps 4-6 of invasion-metastasis cascade
4 - extravasation
5 - colonisation MET
6 - dormancy-proliferation
43
what occurs after the tumour cell destroys the basal membrane
stromal cells express pro-MMP-2
activated by tumour MT1-MMP
activated pro-MMP-2 aid in cell invasion
44
what is ivadipodia
actin-rich membrane protrusions
possess the ECM degrading activity
45
what is epithelial-mesenchymal transitions (EMT)
reversible genetic trans-differentiation
epithelial cells lose E-cadherin and other epithelial markers
mesenchymal markers are expressed
increased cell motility/invasiveness
46
what are the features of developmental EMT
do not divide
resistant to apoptotic signals
retain the ability to generate more than one cell type (stem cell-like)
anoikis resistance
47
what is the pathway to the EMT process
1 - cadherin switch
2 - mucin downregulation
3 - loss of epithelial polarity
4 - increased MMP synthesis
5 - increased mesenchymal markers
48
what is intravasation
entry into the bloodstream
49
what leads to intravasation
reciprocal interactions between tumour associated macrophages (TAM) and tumour cell
50
what do circulating cancer tumour cells interact with
immune cells
51
what are the features of a non-stem cell and cancer stem cells
opposite to non-stem cells:
tumour stem cells - high tumourigenecity, drug resistant, highly metastatic
only tumour stem cell:
self-renewal
anoikis resistance
52
what occurs after intravasation
rolling until it is arrested
arrested by binding its integrins with ICAM1/VCAM1
53
difference between VCAM1 and ICAM
VCAM1 - binds to alpha-4-beta-1 integrin
ICAM1 - alpha-X-beta-2
54
what is the alternative extravasation pathway
trapping - cancer cell is halted in the vessel
microclot - platelets attack the cancer cell
cancer cell makes contact with the basal membrane
cancer cell dissolves the clot
cancer cells proliferate within the vessel
invasion into adjacent tissue
55
what can occur after extravasation
cancer cells can either remain dormant or undergo MET - form secondary tumours
56
what essentially is mesenchymal-epithelial transition (MET)
basically cell colonises an area
then disseminates into multiple many residues
one or more of those residues proliferates a lot then undergoes another wave of metastasis
57
what is the rate limiting step in metastasis
colonisation
58
what are the transcription factors that promote EMT
ZEB1
ZEB2
TWIST
59
how is the MET proposed to be conducted
microRNA's inhibit EMT promoting transcription factors
60
what may be key in inducing EMT-MET
TGFbeta signallling
61
describe the somatic mutation theory (SMT)
cancer begins with a single mutated cell that passes on it genes to its progeny
these cells then acquire further mutations
sub-clones are able to metastasise faster
therefore cancer is mediated by somatic evolution
62
difference between micro and macro-evolution
micro - genetic changes that occur over time in a population
macro - major evolutionary change that occurs at or above species level
63
where has positive selection of mutant clones been observed
blood
skin
oesophagus
64
what is neoplastic progression
the somatic evolutionary process by which a somatic cell develops into cancerous tissue
65
how is clonal-diversity of cancers measured and what is the utility of this
Kaplan-Meier incidence curves
utility towards personalised cancer treatments
66
what is the difference between a driver and passenger mutation
driver - a mutation that directly advantages the clone - tend to cause clonal expansion
passenger - may not linked to any advantage but may be associated because it is in the same genome as the driver - hitchhiker
67
what are the mechanisms that generate genetic diversity
somatic mutagenesis
epigenetic heterogeneity
numerical chromosomal instability
structural chromosomal instability
68
what is branching evolution
from one mutation in one cell to over the course of generations multiple populations of cancer cells with their own genetic characteristics are present in the tumour
69
besides somatic mutation, what are the other 2 theories of cancer
tissue organisational field - tissue disruption leads to cancer
bad luck - unlucky mutations and extrinsic factors lead to cancer
70
what is the ground state theory of cancer
a theory that encapsulates all the other theories
considers their involvement and probability in cancer
71
what is the ideal clinical tool to measure cancer heterogeneity
cost-effective and efficient
sampling to be minimally invasive
no spatial biases
simple proxy biomarkers for assaying
72
what are the dis/advantages of a single biopsy
advantages - cheap, minimally invasive
disadvantages - under-represents heterogeneity
73
what are the dis/advantages of multi-region sampling
advantage - retains spatial information
disadvantages - more invasive, skill required to select region
74
what are the dis/advantages of total-tumour sampling
advantages - global tumour sampling
disadvantages - spatial information is destroyed, material lost to other pathological use
75
what are the dis/advantages of sampling circulating tumour cells (CTC)
advantage - allows serial monitoring, intrinsically retains single cell information
disadvantage - expensive, low sensitivity, selection bias via enrichment of environment
76
what are the dis/advantages of sampling ctDNA
advantage - allows serial monitoring, limited sample preparation
disadvantage - unknown how closely this reflects tumour heterogeneity
77
what is the problem with targeted cancer therapy
they act on the cancer cells for a while until there is another sub-clone driver mutation that renders the therapy ineffective
78
targeted therapy resistance can be solved by using multiple therapies that target different sub-clonal resistance mutations but what is the problem with this
multiple therapies cause toxicity and negative cross-reactivity
79
what is an effective way of controlling tumour and sub-clone mutation resistance to treatment
adaptive therapy:
an intermittent therapy where the cancer is treated but enough to allow a driver sub-clone to take off
this creates competition between the sub-clones until the main one reaches stasis and then you treat again and it repeats
80
what does therapy monitoring involve
genomic material from cancer cells sucha as ctDNA's and CTC's are used to monitor efficacy of therapy and emergence of resistant sub-clones
81
what are the advantages of glycolysis to a proliferating cell
although inefficient is rapid
waste product - lactate is recycled into the cori cycle in the liver
82
how does pyruvate enter the mitochondria
as acetyl-CoA
83
what happens when acetyl-CoA enters the mitochondria
donates electrons to NAD/FAD in the TCA cycle to generate NADH/FADH
84
what happens once FADH/NADH are generated
they transport the electrons to pass through the ETC to generate the proton gradient required for ATP synthase
85
what occurs if the ETC's chains activity is greater than the ATP need
respiratory complexes leak electrons to O2 to produce superoxide
damages nucleic acids/lipids /proteins
86
what is used to neutralise the ROS (superoxide)
NADPH from the pentose phosphate pathway is required to neutralise ROS
87
what is the pentose phosphate pathway also required for
DNA/RNA synthesis
88
features of PKM1
most common enzyme in normal tissue
quite active
channels pyruvate (its product) to pyruvate dehydrogenase (mitochondrial enzyme)
89
features of PKM2
prevalent in cancer cells
less active than PKM1
channels pyruvate to lactate dehydrogenase (cytosolic enzyme)
90
what are the effects of PKM2 on ROS
PKM2 functions to suppress ROS synthesis by restricting pyruvate access into the mitochondria
increases glycolytic intermediates to fuel the pentose phosphate pathway - also suppresses ROS via NADPH
91
what is PKM2 expression regulated by
alternative mRNA splicing
92
why is PKM2 expression upregulated in cancer cells
c-myc is an oncogene that is deregulated in cancer
promotes expression of splicing factors
promotes PKM2 expression
93
what does myc drive
drives glutamine and glucose metabolism
94
what directly drives anabolic metabolism
oncogenic growth signalling
95
effect of p53 on the pentose phosphate pathway
suppresses glycolysis
therefore promotes the PPP
96
how does p53 effect mitochondrial respiration
promotes it
97
