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BioMed Season Finale Part 1 > Pathology - Cancer > Flashcards

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

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2
Q

what is apoptotic blebbing

A

in an apoptotic cell the light is fragmented unevenly compared to a non-apoptotic spherical cell

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3
Q

what does apoptotic blebbing lead to

A

pykonisis

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4
Q

what is DNA damage detected by

A

p53

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5
Q

what does p53 activate when it detects DNA damage

A

Bax

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6
Q

function of Bax

A

creates holes in the mitochondria - releases signaling molecules

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7
Q

what to the signaling molecules in from mitochondria activate

A

Caspase 9

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8
Q

function of Caspase 9

A

cleaves an activates Caspase 3/6/7

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9
Q

what is the function of cleaved Caspase 6/3/7

A

cleaves I from CAD in ICAD - leads to active conformation CAD

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10
Q

function of CAD

A

DNA fragmentation
protein cleavage
nuclear membrane loss
organelle breakdown

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11
Q

what are is the sequence that leads to Caspase 8 activation

A

Extrinsic stimuli
Death cell receptor

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12
Q

what does Caspase 8 activate specific to Type I extrinsic pathway

A

tBid

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13
Q

function of tBid

A

releases mitochondrial contents - act as signaling molecules

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14
Q

what does Caspase 8 cleave which is common in all apoptotic processes

A

Caspase 6/3/7

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15
Q

what happens when effector caspases are activated

A

substrate cleavage
further initiator caspase activation

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16
Q

what are the initiator caspases

A

Caspase 9/8 and also 10 (rare)

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17
Q

what are the effector Caspases

A

Caspase 3/6/7

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18
Q

what is DISC

A

multi-protein complex responsible for caspase 8 activation via the extrinsic pathway

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19
Q

what happens when cytochrome c is released into the cytoplasm

A

binds to APAF-1

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20
Q

what does the binding of APAF-1 and cytochrome c lead to

A

an apoptosome - wheel of death

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21
Q

what binds to the apoptosome

A

Caspase 8

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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

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23
Q

function of the BH3 domain

A

makes a pore in the mitochondrial membrane to release its contents

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24
Q

how is Bim de-activated

A

degraded by a proteosome

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25
Q

how is Bmf imobillised

A

sequestrated by the cytoskeleton - binds via DLC-2

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26
Q

how is Bad inactivated

A

many growth factors phosphorylate Bad

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27
Q

what is targeted therapy to promote apoptosis

A

target Bcl-2 with a BH3 mimetic to bind to Bcl-2

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28
Q

how is glucose uptake affected in breast cancer cells

A

invasive cells have increased glycolysis compared to hypoxia-induced decrease in glycolysis in non-invasive cells

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29
Q

what is the hypoxia-mediated selection hypothesis

A

increased aerobic glycolysis makes the tumour cells more likely to survive periods of low oxygen

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30
Q

what is the reversible regulation of glycolysis regulated by

A

PFK1-phosphofructokinase - its the rate-limiting enzyme in glycolysis

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31
Q

what is PFK1 activated and inhibited by

A

inhibited by ATP
activated by AMP

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32
Q

what are the function of PHD’s

A

they are oxygen-dependent prolyl hydroxylases that hydroxylate HIF1alpha

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33
Q

what happens once HIF1alpha is hydroxylated

A

pVHL is recruited to HIF1aplha
this targets HIF1aplha for proteome-dependent degradation

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34
Q

what is HIF1alpha

A

a transcription factor for expression of glycolysis and autophagy (cell eating itself) when no oxygen

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35
Q

do you get how oxygen presence leads to decreased glycolysis and autophagy

A

yes

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36
Q

how dos oxygen depletion effect PFK1 expression

A

increase in HIF1alpha leads to increase in PFK1to increase glycolysis

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37
Q

what is irreversible regulation of glycolysis

A

mutation in fumarate hydratase (FH) and succinate dehydrogenase (SDH)

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38
Q

how do mutations in FH and SDH cause cancer

A

they inhibit PDH’s which increase HIF1alpha expression which leads to increased glycolysis and other hallmarks of cancer

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39
Q

what are the functions of metalloproteinases (MMP’s) in metastasis

A

break down extracellular membrane and cell adhesion molecules

40
Q

difference between secreted and transmembrane MMT’s

A

secreted - are used to degrade nearby cells
transmembrane - are used for the invasion of the tumour cell

41
Q

what are the first 3 steps of invasion-metastasis cascade

A

1 - breaking down basal membrane
2 - EMT and intravasation
3 - anoikis resistance

42
Q

what are steps 4-6 of invasion-metastasis cascade

A

4 - extravasation
5 - colonisation MET
6 - dormancy-proliferation

43
Q

what occurs after the tumour cell destroys the basal membrane

A

stromal cells express pro-MMP-2
activated by tumour MT1-MMP
activated pro-MMP-2 aid in cell invasion

44
Q

what is ivadipodia

A

actin-rich membrane protrusions
possess the ECM degrading activity

45
Q

what is epithelial-mesenchymal transitions (EMT)

A

reversible genetic trans-differentiation
epithelial cells lose E-cadherin and other epithelial markers
mesenchymal markers are expressed
increased cell motility/invasiveness

46
Q

what are the features of developmental EMT

A

do not divide
resistant to apoptotic signals
retain the ability to generate more than one cell type (stem cell-like)
anoikis resistance

47
Q

what is the pathway to the EMT process

A

1 - cadherin switch
2 - mucin downregulation
3 - loss of epithelial polarity
4 - increased MMP synthesis
5 - increased mesenchymal markers

48
Q

what is intravasation

A

entry into the bloodstream

49
Q

what leads to intravasation

A

reciprocal interactions between tumour associated macrophages (TAM) and tumour cell

50
Q

what do circulating cancer tumour cells interact with

A

immune cells

51
Q

what are the features of a non-stem cell and cancer stem cells

A

opposite to non-stem cells:
tumour stem cells - high tumourigenecity, drug resistant, highly metastatic
only tumour stem cell:
self-renewal
anoikis resistance

52
Q

what occurs after intravasation

A

rolling until it is arrested
arrested by binding its integrins with ICAM1/VCAM1

53
Q

difference between VCAM1 and ICAM

A

VCAM1 - binds to alpha-4-beta-1 integrin
ICAM1 - alpha-X-beta-2

54
Q

what is the alternative extravasation pathway

A

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
Q

what can occur after extravasation

A

cancer cells can either remain dormant or undergo MET - form secondary tumours

56
Q

what essentially is mesenchymal-epithelial transition (MET)

A

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
Q

what is the rate limiting step in metastasis

A

colonisation

58
Q

what are the transcription factors that promote EMT

A

ZEB1
ZEB2
TWIST

59
Q

how is the MET proposed to be conducted

A

microRNA’s inhibit EMT promoting transcription factors

60
Q

what may be key in inducing EMT-MET

A

TGFbeta signallling

61
Q

describe the somatic mutation theory (SMT)

A

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
Q

difference between micro and macro-evolution

A

micro - genetic changes that occur over time in a population
macro - major evolutionary change that occurs at or above species level

63
Q

where has positive selection of mutant clones been observed

A

blood
skin
oesophagus

64
Q

what is neoplastic progression

A

the somatic evolutionary process by which a somatic cell develops into cancerous tissue

65
Q

how is clonal-diversity of cancers measured and what is the utility of this

A

Kaplan-Meier incidence curves
utility towards personalised cancer treatments

66
Q

what is the difference between a driver and passenger mutation

A

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
Q

what are the mechanisms that generate genetic diversity

A

somatic mutagenesis
epigenetic heterogeneity
numerical chromosomal instability
structural chromosomal instability

68
Q

what is branching evolution

A

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
Q

besides somatic mutation, what are the other 2 theories of cancer

A

tissue organisational field - tissue disruption leads to cancer
bad luck - unlucky mutations and extrinsic factors lead to cancer

70
Q

what is the ground state theory of cancer

A

a theory that encapsulates all the other theories
considers their involvement and probability in cancer

71
Q

what is the ideal clinical tool to measure cancer heterogeneity

A

cost-effective and efficient
sampling to be minimally invasive
no spatial biases
simple proxy biomarkers for assaying

72
Q

what are the dis/advantages of a single biopsy

A

advantages - cheap, minimally invasive
disadvantages - under-represents heterogeneity

73
Q

what are the dis/advantages of multi-region sampling

A

advantage - retains spatial information
disadvantages - more invasive, skill required to select region

74
Q

what are the dis/advantages of total-tumour sampling

A

advantages - global tumour sampling
disadvantages - spatial information is destroyed, material lost to other pathological use

75
Q

what are the dis/advantages of sampling circulating tumour cells (CTC)

A

advantage - allows serial monitoring, intrinsically retains single cell information
disadvantage - expensive, low sensitivity, selection bias via enrichment of environment

76
Q

what are the dis/advantages of sampling ctDNA

A

advantage - allows serial monitoring, limited sample preparation
disadvantage - unknown how closely this reflects tumour heterogeneity

77
Q

what is the problem with targeted cancer therapy

A

they act on the cancer cells for a while until there is another sub-clone driver mutation that renders the therapy ineffective

78
Q

targeted therapy resistance can be solved by using multiple therapies that target different sub-clonal resistance mutations but what is the problem with this

A

multiple therapies cause toxicity and negative cross-reactivity

79
Q

what is an effective way of controlling tumour and sub-clone mutation resistance to treatment

A

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
Q

what does therapy monitoring involve

A

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
Q

what are the advantages of glycolysis to a proliferating cell

A

although inefficient is rapid
waste product - lactate is recycled into the cori cycle in the liver

82
Q

how does pyruvate enter the mitochondria

A

as acetyl-CoA

83
Q

what happens when acetyl-CoA enters the mitochondria

A

donates electrons to NAD/FAD in the TCA cycle to generate NADH/FADH

84
Q

what happens once FADH/NADH are generated

A

they transport the electrons to pass through the ETC to generate the proton gradient required for ATP synthase

85
Q

what occurs if the ETC’s chains activity is greater than the ATP need

A

respiratory complexes leak electrons to O2 to produce superoxide
damages nucleic acids/lipids /proteins

86
Q

what is used to neutralise the ROS (superoxide)

A

NADPH from the pentose phosphate pathway is required to neutralise ROS

87
Q

what is the pentose phosphate pathway also required for

A

DNA/RNA synthesis

88
Q

features of PKM1

A

most common enzyme in normal tissue
quite active
channels pyruvate (its product) to pyruvate dehydrogenase (mitochondrial enzyme)

89
Q

features of PKM2

A

prevalent in cancer cells
less active than PKM1
channels pyruvate to lactate dehydrogenase (cytosolic enzyme)

90
Q

what are the effects of PKM2 on ROS

A

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
Q

what is PKM2 expression regulated by

A

alternative mRNA splicing

92
Q

why is PKM2 expression upregulated in cancer cells

A

c-myc is an oncogene that is deregulated in cancer
promotes expression of splicing factors
promotes PKM2 expression

93
Q

what does myc drive

A

drives glutamine and glucose metabolism

94
Q

what directly drives anabolic metabolism

A

oncogenic growth signalling

95
Q

effect of p53 on the pentose phosphate pathway

A

suppresses glycolysis
therefore promotes the PPP

96
Q

how does p53 effect mitochondrial respiration

A

promotes it

97
Q
A

BioMed Season Finale Part 1 (13 decks)

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