cancer and angiogenesis Flashcards
1
Q
what are the 5 main forms of cancer contributing to world wide mortality
A
lung stomach liver colorectal breast
2
Q
in normal tissues you have a balance of rate of growth and rate of death. in cancer this is …..
A
disrupted
3
Q
what is a neoplasm
A
abnormal mass of tissue, growth of which exceeds and is uncoordinated with normal tissues
4
Q
what is a tumour
A
non-specific term meaning lump or swelling
5
Q
what is cancer
A
any malignant neoplasm or tumour
6
Q
what does metastasis mean
A
discontinuous spread of malignant neoplasm to distant sites
7
Q
what happens in neoplasia at the cellular level (3)
A
excessive cellular proliferation
uncoordinated growth
tissue infiltration
8
Q
what happens in neoplasia at the molecular level (2)
A
disorder of growth regulatory genes
develops in a multistep fashion
9
Q
there is an estimate of how many driver mutations in key genes that are required for cancer
A
5-15
10
Q
what does p53 do
A
stops cell cycle to enable repair to occur. if repair doesnt happen it trigger apoptosis
11
Q
what is Rb and what does it do
A
retinoblastoma protein - stops the cell cycle
frequently it is absent or mutated in cancer
12
Q
what are proto-oncogenes
A
normal genes whose protein product promotes growth
13
Q
a proto-oncogene is turned into an oncogene as a consequence of what (3)
A
mutation
chromosomal rearrangement
gene amplification
14
Q
what is a transcription factor that is amplified around 1000 fold in many cancers
A
Myc
15
Q
point mutation at glycine 12 to any other amino acid locks what in the hyperactive permanently on state
A
Ras
16
Q
what are tumour supressor genes
A
genes that encode proteins that discourage cell growth
17
Q
there are 2 main pathways of apoptosis. these are:
A
intrinsic and extrinsic
18
Q
what are the key steps to the intrinsic apoptosis pathway
A
recognition of damage by p53
upregulation of BAX (pro-apoptotic protein - usually inhibited by Bcl-2)
cytochrome C released from mitochondria and binds to APAP1 with caspase 9 in centre
19
Q
what do cancer cells upregulate in regard to the intrinsic apoptotic pathways
A
Bcl-2
20
Q
how does the extrinsic pathway of apoptosis occur
A
signals from outside bind to the death receptor
21
Q
what do cancer cells mutate in regard to the extrinsic apoptotic pathway
A
the death receptor
22
Q
what is the original two hit hypothesis of cancer
A
1st event - initiation
2nd event - promotion
23
Q
the alternative theory is that multiple hits occur and that there is a lag time between exposure (1st hit) and deelopment of clinically apparent cancer
A
T
24
Q
what are the hallmarks of cancer (6)
A
sustaining proliferative signalling evading growth supressors activation invasion and metastasis enabling replicative immortality inducing angiogenesis resisting cell death
25
what are the emerging hallmarks of cancer
deregulating cellular energetics - use glycolysis instead of oxidative phosphorylation
avoiding immune destruction
26
what are the enabling characteristics that allow all the hallmarks of cancer to occur
genome instability and mutation
| tumour promoting inflammation
27
what is angiogenesis
the development of new blood vessels from the existing vasculature
28
angiogenesis is found in over 50 diseases including (3)
chronic inflammatory disease
vascular malformations
cancer
29
which blood vessels are more likely to respond to angiogenesis signals
capillaries
30
what are endothelial cells naturally held in check by balance of
pro-angiogeneic promoters (VEGF, PDGF, FGF) and anti-angiogenic inhibitors (thrombospondin 1)
31
why cant tumours grow beyond 1-2mm cubed without a blood supply
due to diffusion limits of oxygen and nutrients
32
as tumours grow they alter their microenvironment this includes (4)
pH
concentration of nutrients
increase in interstitial pressure
decrease in oxygen tension (hypoxia)
33
cells respond to the changes in tumour microenvironment by generating what
angiogenic molecules eg VEGF to extend blood vasculature to relieve pressure
34
why is tumour angiogenesis such a problem
- it supports growth of a tumour by providing nutrients and gas exchange
- it allows tumours to invade their surroundings
- it promotes metastasis
35
what are the steps in tumour induced spouting angiogenesis
1. release of angiogenic factors
2. activation of endothelial cells
3. matrix degradation
4. release of cell-matrix contacts
5. endothelial cell migration and invasion
6. endothelial cell proliferation
7. lumen formation
8. capillary formation
9. vascular stabilisation
36
the first step of tumour induced sprouting angiogenesis is the release of angiogenic factors this is in response to certain conditions such as
stress
hypoxia
hormones
37
hypoxia results in the translocation of HIF-1alpha and HIF-1beta to nucleus where they act as transcription factor for genes containing a hypoxia response element in their promoters. what is a prime example of one of these genes
VEGF
38
what is VEGF
vascular endothelial growth factor
| most abundantly expressed angiogenic factor
39
there are various isoforms of VEGF, which is the most common
VEGF165
40
VEGF bind to VEGFR2 on surface of endothelial cells. which signalling pathway is activated
Ras and MAPK pathway via Grb2
41
activation of the Ras MAPK pathway by VEGF leads to what
matrix breakdown, proliferation, migration, permeability and tube formation
42
in the 3rd step of tumour induced sprouting angiogenesis the matrix is degraded. what is commonly upregulated in this step
MMPs and TIMPs
43
what are MMPs
matrix metalloproteins - cleave ECM components. regulate EC attachment, migration and proliferation
44
what are TIMPs
tissue inhibitors of MMPs
| block angiogenic response
45
why is a balance required between MMPs and TIMPs in angiogenesis
when the level of proteolysis is too high, angiogenesis is inhibited
46
step 4 of the tumour induced sprouting angiogenesis requires that endothelial cells change their what
integrins
47
tumour cells down regulate and upregulate which integrins
downregulate alpha2beta1
| upregulate alpha5beta1
48
what do integrins mediate
cell migration and cell adhesion to a variety of matrix proteins
49
what does binding growth factors to endothelial cells cause
Down regulation of integrins for basement membrane alpha2beta1
Up regulation of integrins for extracellular matrix alpha5beta1
50
in step 5 of tumour induced sprouting angiogenesis, MMPs degrade the basement membrane allowing cells to invade through it. endothelial cells migrate into area that requireds new vessels through a conc gradient of what
chemoattractants including VEGF
51
in step 6 of tumour induced sprouting angiogenesis endothelial cells enter the cell cycle to replicate and provide enough new cells for the new vessels to grow. which cell leads the way
tip cell
52
lumen fromation depends on whether its what
single cellular strand or double cellular strand
53
lumen formation of single cellular strand and double cellular strand both start with what
pinocytosis - pinching of the membrane
54
what are the steps to lumen formation in single cellular strand
- pinocytosis
- vesicles form
- vesicles fuse
- vesicles line up along central line
- get vacuole fusion
- exocytosis and luminal expansion
55
what are the steps to lumen formation in double cellular strand
- pinocytosis
- repolarisation of cell
- vesicular fusion
- vacuolar fusion
- luminal expansion
56
in step 8 of tumour induced sprouting angiogenesis capillaries are formed. endothelial cells differentiate. vacuoles join to form lumen and anastamosis occurs. what does this mean
joining of many capillaries
57
in the final step of tumour induced sprouting angiogenesis is vascular stabilisation. endothelial cells lay down basement membrane followed by the recruitment of what
pericytes and smooth muscle cells
58
how do tumour vessels differ from normal vessels
- increased vessel number per area
- more proliferating endothelial cells
- decreased endothelial cell-cell adhesion (easier route for metastasis)
- leaky vessels
- decreased vessel stability
- loss of close association of basement membrane with endothelial cells
59
why is angiogenesis important
- results in increased oxygen and nutrients for tumour cell
| - by increasing the number of vessels in a tumour, more cancer cells can escape
60
what is sprouting angiogenesis
production of new vessels from existing vasculature (cancer cells being stressed upregulating HIf then VEGF, VEGF bind to receptor on endothelial cells, endothelial cells being activated by VEGF signalling pathway, producing MMPs to breakdown basemen membrane, EC changing integrin expression, migrating and then proliferation and then forming the lumen and joining up)
61
delivery of blood borne agents to tumour cell targets in solid tumours has proven difficult due to:
abnormal blood flow
lack of lymph damage
high interstitial pressure (hard for things to move in)
poor access to majority of tumour mass
62
tumour cells are inherently unstable and quickly become resistant to therapy T/F
T
63
occlusion of a single vessel has the potential for killing many tumour cells T/F
T
64
when targetting tumour blood vessels resistance is less likely to develop - why
endothelial cells are not malignant
65
what makes a good drug
```
specificity
preferable oral administation
hydrophilic
good pharmokinetics
not toxic
```
66
how do you test a new drug
relevant in vitro studies
pre clinical in vivo studies
clinical trials
67
what are the stages of clinical trials
o Phase one – small group (last attempt of treatment). Looking at side effects and dosage, how best to give the drug (pill or injection)
o Phase two – effectiveness of drug and the safety
o Phase three – randomised controlled trials 300+ people
68
what are the potential study end points in phase 3 trials
```
LOW:
response rate
progression free survival
overall survival
quality of life
cost effectiveness
```
69
what is • response evaluation criteria in solid tumours (RECIST)
a set of published rules that define tumour response rate
70
what are the advantages and disadvantages of using response rate
adv - early primary endpoint
dis - poor correlation with overall survival
subjective measurement
71
what are the advantages and disadvantages of using progression free survival
adv - early primary endpoint
dis - poor correlation with overall survival
subjective measurement
72
what are the advantages and disadvantages of using overall survival
adv - direct measurement of quantity of life
objective - easy to measure
dis - late primary endpoint
potential confounding effects of post progression therapy
73
what is bevacizumab
humanised monoclonal antibody
| blocks binding of VEGF to its main receptors
74
the clinical trials do not show the same promising efficacy that in vivo studies show but some stabilisation of disease has been reported T/F
T
75
why is there a difference in the results of in vivo studies and clinical trials of bevacizumab
• established, slow growing tumours have different angiogenic requirements to fast growing tumours
o phase 3 patients had tumours for a while whereas mice have fast growing tumours
• dose choice: Use upper limiting dose (maybe its not the best dose)
• administration protocol – differences in 2 dosage schedule
• drugs have varied effects on different tumours
• assessed by effect on tumour shrinkage (RECIST)
• tumours out smart antiangiogenic therapy – multiple pro angiogenic factors. Multiple cross talk/cross regulation
76
how does bevacizumab work
pruning of abnormal tumour vaculature
functional normalisation leads to reduced interstitial pressure
decrease in tumour hypoxia
77
which cancers is bevacizumab approved for
metastatic colorectal cancer and lung cancer
78
approval of bevacizumab was withdrawn for which cancer in 2011
breast cancer
79
why was bavacizumab withdrawn for use in breast cancer
Increasing progression free survival but overall survival not increasing – end of life much more vigorous/damaging
80
what is the aim of cancer treatment in patients with advanced disease
* Improve quantity of life
| * Improve quality of life
81
Why does treatments that increase Progression Free Survival fail to improve Overall Survival
- insufficient statistical power to detect significant difference
- measurement of progression is imprecise whereas date of death is exact
- biological effects
- effect of post progression therapy
82
• As the tumour endothelium is genetically stable it was predicted that resistance to antiangiogenic therapy would develop slowly. in fact,
it develops rapidly
83
what are the 7 ways in which tumours can escape from treatment control
1. hypoxia increases pro-angiogenic factor production
2. vascular normalisation
3. vascular mimicry
4. expression of multiple angiogenic factors
5. recruitment of bone marrow derived cells
6. selection of metastatic cancer cells
7. vessel co-option
84
what is vascular normalisation
better blood flow into tumour so it can grow
85
what is vascular mimicry
when vessels have been pruned, left with a channel. tumour cells mimic the blood vessels so still get blood flow where channel was
86
what are bone marrow derived cells also known as and what can they do
endothelial progenitor cells. can form new cessels in a way that isnt angiogenesis
87
selection for metastatic cancer cells is caused by cancer cells being stressed and therefore more likely to become...
metastatic
88
what is vessel cooption
when tumour cells grow around cells that are already there
89
one resistance mechanism to inhibiting VEGF is using an alternative signalling pathway for angiogenesis. what are the examples
```
other VEGF isoforms
NRPs
PIGF
FGF
TGFbeta
integrins
```
90
reduced tumour blood flow may lead to a more hostile tumour environment that promotes tumour invasion and metastasis T/F
T
91
when there is increasing amounts of hypoxia the tumour looks like its getting inhibited so get increased progression free survival. but then what happens
get upregulation of alternative factors
tumour cells adapt to hypoxia
grows faster than it would have done if left alone
