Cancer Flashcards
(95 cards)
1
Q
Characteristics of Cancer Cells
A
- lack of controlled growth
- loss of specialised functions
- less adhesive to other cells and extra cellular matrix
- can metastasise
2
Q
Oncogene mutations require how many mutated alleles and how does their function alter
A
- dominant manner (only one allele needs to be mutated for pre-disposition of cancer)
- gain of function mutations
3
Q
Mutations in tumour suppressor genes require how many alleles to be mutated for an individual to be predisposed to cancer and how does this alter the genes functions
A
- loss of function mutations
- both alleles need to be mutated (two hypothesis hit) for predisposition
(Can be acquired or inherited through somatic mutations)
4
Q
Stages of metastasis
A
- Benign tumour in primary location, angiogenesis, proliferation
- Metastatic sub clone of tumour breaks through basal lamina and passes through ECM
- Intravasation, interacts with host lymphoid cells
- Tumour cells embolus
- Adhesion to basement membrane of endothelial cells in blood vessels
- Extravasation, growth at secondary site and angiogenesis occurs at new site as well
5
Q
Def: Mortality
A
death
6
Q
Def: morbidity
A
disease or ill health
7
Q
What is burden of disease and the equation
A
quantifies the gap between populations actual health to ideal health in a given year
= time lost due to mortality + time lost due to disability
8
Q
What is disability adjusted life years (DALY) and its equation
A
Years of lost life (premature mortality) + Years lost to disability (due to injury or illness)
one DALY = one year of healthy life lost due to illness/death
9
Q
What is the association of DALY and Burden of disease
A
the higher the DALY with a particular disease/injury = the greater the burden of that disease
10
Q
Which sex and age experiences greater burden with an associated disease
A
Males
burden increases with age (highest at 65-84)
11
Q
Which disease has the highest burden of disease
A
Cancer
12
Q
cancer incidence and mortality increases with….
A
age
13
Q
what are the two heritable properties of cancer cells
A
- unrestrained growth
2. invade and colonise (like the white people)
14
Q
Cancer cell morphology characteristics
A
- large variable shaped nuclei
- small cytoplasmic volume
- variation in size and shape
- disorganised arrangement of cells
- loss of normal specialised features
- elevated expression of particular cell markers
- large number of dividing cells
- poorly defined tumour boundaries
15
Q
What are the two forms of tumours
A
- benign (non invasive)
2. malignant (cancer)
16
Q
tumour size and associated detection
A
X ray detectable
- 10^8 cells
palpable
- 10^9 cells
therefore many cells need to be cancerous before detection
17
Q
What does the tumour need for development and how does this occur
A
a blood supply
occurs through angiogenesis
- vascular endothelial growth factor is released by tumour which increases blood vessel expression
- matrix metalloproteases (MMP’s) are also released for movement of vessels through ECM
18
Q
When is the earliest that cancer can be detected (cell number) and what ways is cancer detected?
A
10^8 cells (1 billion) at detection
ways:
- mammography
- X ray
- biopsy
- detection of tumour antigens
19
Q
Treatment of cancer
A
early intervention allows for
- surgery
- hormone therapy
- chemotherapy
- targeted drug therapy
- radiotherapy
20
Q
what is the relationship between cancer development and genetic factors
A
mutations accumulate in different genes which increases the development of cancer gradually
- initiation
- normal cell to initiated cell - promotion
- initiated cell to cancer cell (differentiated) - progression
- differentiated cancer cell to undifferentiated and invasive cancer cell
21
Q
What is the environment inside a tumour cell
A
low oxygen levels
scarce nutrients
high acidity
- due to increased lactic acid from glycolysis
natural barriers to growth
- surrounded by normal cells
22
Q
When do selective advantages for cancers begin
A
take years to develop and vary for each cancer and individual
examples:
- leukaemia 5-8 years
- lung cancer 10-20 years
- prostate cancer 10+ years
23
Q
CERVICAL CANCER
what is cervical cancer? main cause? symptoms?
A
WHAT:
- excess prolif of squamous epithelial cells in neck of womb (cervix)
CAUSE:
HPV is a risk factor in 90% of cases
SYMTPOMS:
early stages:
- asymptomatic
- areas of dysplasia (detectable on pap smear)
later stages:
- dysplasia becomes more advanced (may lead to malignant cervical carcinoma)
24
Q
CERVICAL CANCER
detection?
A
pap smear
cervical screening test
- evidence of HPV infection
25
Genetic changes in cancer
genetically unstable
| - accumulate mutations and chromosomal abnormalities at higher rate than normal cells
26
Epigenetic changes in cancer
changes which are not in the nucleotide sequence of DNA:
1. unusual nucleus apparence
- histones not acetylated
- large amount of heterochromatin
- DNA tightly packed (no gene expression)
2. DNA methylation
- gene expression switched off
27
How does apoptosis contribute to cancer
normal mechanisms to induce apoptosis are switched off
28
How can stem cells give rise to cancer cells
mutations can occur in stem cells which can lead to cancerous stem cell
29
What are oncogenes
normal gene which when mutated has involvement in cancer development
oncogenes produce oncoproteins
30
what can cause oncogenes
- viruses
- chemicals
- radiation
31
What factors may result in oncogenes
over-expressed proteins
reduced expression of proteins
defective proteins
32
Aetiology of Rous sarcoma virus
RNA retrovirus
- uses reverse transcriptase to generate DNA intermediates
- inserts into hist genome (provirus)
gene = src
- involved in regulation of cell growth and differentiation
- becomes mutated by virus creating (v-src)
- not needed for viral replication but transforms cell leading to
cancer
33
what does src gene encode for and how does v-src alter normal functioning
non receptor tyrosine kinase (signalling molecule)
v-rsc = constantly activated
- activating kinase signalling cascades
- decreased adhesion of cell to surface
- increased uncontrolled growth
- loss of contact inhibition
- increased transport of metabolites
34
How does the avian leokosis virus differ in mechanisms to the Rous sarcoma virus
instead of creating an oncogene this virus inserts its DNA next to a proto-oncogene
- acts as a strong promotor or enhancer for the gene
proto-oncogene c-myc (DNA binding protein - transcription factor)
- increases expression of c-myc
35
What is a class of receptors which are susceptible to mutations in cancers? what is the normal structure and function of these receptors? How does this defer when mutated?
RECEPTOR CLASS:
receptor tyrosine kinases (RTK's)
NORMAL STRUCTURE:
transmembrane protein with intra and extracellular domains
NORMAL FUNCTION:
receptors for growth factors and begin signal transduction pathways once growth factors bind
MUTATED STRUCTURE/FUNCTION:
result in continually active receptors even in the absence of ligands (growth factors)
36
Common defective receptor tyrosine kinases
Erb-B family (AKA EGFR)
| - Her2 is part of the family and common in breast tumors
37
Receptor tyrosine kinase general signaling pathway
the receptor have tyrosine kinase domains (particular part of the intracellular portion of protein) which become phosphorylated when the ligand binds
this activates RTK allowing other intracellular signalling proteins to bind become phosphorylated and then activated
38
What happens when Erb-B (epidermal growth factor receptor EGFR) family becomes mutated
the extracellular domain becomes missing due to a truncated receptor
this means that it is constitutively active
leading to uncontrolled growth
39
what is p53 and what is its normal function
p53 is a tumour suppressor transcription factor
NORMAL FUNCTION:
- regulated cell cycle by activating other transcription factors and recognises DNA damage
- conserves stability of genome by preventing mutations through:
- triggering growth arrest, DNA repair or apoptosis (when cannot be
repaired)
40
Normal p53 pathway
WHEN P53 IS NOT NEEDED:
1. bound to Mdm2
- Mdm2 promotes it ubiquitylation and degradation in proteasomes
WHEN P53 IS NEEDED (DNA DAMAGE):
1. p53 becomes phosphorylated which blocks the binding of Mdm2
2. p53 binds to regulatory region of p21 gene which stimulates its expression
3. p21 binds to G1/S Cdk
- G1/S Cdk allows cell to continue in cell cycle
4. G1/S Cdk becomes inactive triggering cell cycle arrest until damage is fixed
41
Mutated p53 pathway
p53 becomes non-functional (cannot be phosphorylated therefore stays bound to Mdm2
- this leads damaged cells to continue in cell cycle which may lead to cancer
42
What is the APC protein
adenomatous polyposis coli
tumour supressor transcription factor
43
What are APC's 2 main roles
1. inhibits myc gene (transcription factor) expression
- myc induces expression of many genes required for cell to
progress from G1 to S phase in cell cycle
2. Degradation of B-catenin
- B-catenin has 2 roles:
- cell to cell adhesion
- drives transcription of target genes involved in cell proliferation
- mutations which activate B-catenin are found in many cancers
44
What are the consequences of mutations in the APC protein
no control of myc or B-catenin expression allowing cells to continue in the cell cycle even when damaged
this can cause cancer
45
COLORECTAL CANCER
what are the precancerous growths that form? where do they form?
polyps which form on the inside wall of the colon
46
COLORECTAL CANCER
What mutations are needed for precancerous growths to become cancer? How many mutations required?
1. polyps contain APC mutations
2. if polyps undergo a Ras mutation
- more uncontrolled cell division
3. another mutation in p53
- malignant carcinoma
therefore 3 MUTATIONS NEEDED
47
COLORECTAL CANCER
How are the APC mutations acquired
INHERITED:
1. one APC allele mutation is inherited (familial adenomatous polyposis)
2. only one more APC mutation = formation of polyps
OTHER PATIENTS:
acquire 2 mutations during life
48
What are G proteins and what are the 2 types
```
signal transduction proteins apart of the GTPase class
- largest class of oncoproteins
```
2 types:
1. heterotrimeric complexes
2. small monomeric GTPases (e.g. Ras)
49
G proteins function pathway
1. hormone binds to receptor
2. which then binds to GDP bound G protein
3. when bound GDP is replaced by GTP and the subunits of G proteins dissociate
4. G protein subunit binds to adenlate cyclase
5. Adenlyl cyclase then converts ATP to activate cAMP
50
What mutation causes Ras oncoprotein?
a single base change in normal proto-oncogene
| - changes glycine amino acid to valine
51
What changes in Ras function when it becomes mutated
loss of GTPase activity due to:
| - an increased time Ras are bound to GTP which turns signalling pathway on for a lot longer
52
What is the Ras pathway
1. Ras protein lies inactive on cellular membrane bound to GDP
2. phosphorylated RTK causes binding of adaptor protein
3. adaptor protein becomes activated allowing Ras-activating protein to bind to it
4. Ras activating protein causes GDP to be replaced with GTP activating Ras protein
53
What are the 3 main cell types found in skin
1. basal cells (lower layer)
2. squamous cells (top layer)
3. melanocytes (produces melanin which colours skin)
54
What are the 2 types of skin cancer
1. melanoma of skin
- begins in melanocytes
2. non-melanoma skin cancer (NMSC)
- basal cell carcinoma (BCC)
- squamous cell carcinoma (SCC)
55
NON MELANOMA SKIN CANCER
Where does basal cell carcinoma most often occur and why
WHERE:
- head
- neck
- arms
WHY:
high UV exposure in these areas
56
NON-MELANOMA SKIN CANCER
what happens cellular wise in basal cell carcinoma? What is the rate of its growth and does it spread?
basal cells invade the dermis (where squamous cells lie)
slow growth
usually does not spread
57
NON MELANOMA SKIN CANCER
Where does squamous cell carcinoma usually occur? what is its growth rate? can it spread?
head, neck and arms
fast growing
can spread
58
MELANOMA CANCER
exposure to ..... increases risk
UV
59
MELANOMA
Diagnosis
```
A - asymmetry (irregular)
B- boarders (uneven)
C- colour (variegated)
D- diameter (>6mm)
E- evolving (changing and growing over time)
```
60
What is metastasis
development of secondary growths at a different site than primary tumour
61
Mechanisms of metastasis
cancer cells secrete proteases which digest ECM
selectins on endothelial cells recognise carbohydrate groups on cancer cells allowing them to adhere to endothelial cells at new site of the body
62
E-cadherin function in normal cells
links cells together at the side and connects to cytoskeleton within cell
- B-catenin links E-cadherin to cytoskeleton
63
How does E-cadherins change in cancer cells
E-cadherin expression is reduced or located in cytoplasm no the membrane
this causes a breakdown in cell to cell adhesion
64
What are integrins and what is their function
integrins enable cells to link to extracellular matrix at basal surface
- also bind to cytoskeleton
65
How do integrins differ in cancer
reduced adhesion of cells to basal lamina
alpha5beta3 integrin have elevated expression in metastasising cells
- alpha5beta3 have a wide specificity and therefore cells can move over wider range of surfaces
66
Loss of E-cadherin or integrins cause cells to become more
motile
67
What is the role of proteases?
regulate composition of extracellular molecules
endopeptidases are secreted by proteases
-breaks down peptide bonds between amino acids
68
What are the 2 types of proteases?
serine proteases
- plasminogen
metalloproteinases
- collagenase
- stromelysin
69
How does the ECM balance the function of proteases
protease inhibitors
70
How are proteases secreted in both types
Both secreted as inactive forms which become activated
e. g. serine proteases
- secreted as precursor plaminogen
- becomes activated (plamin) by plaminogen activators
71
How are metalloproteinases classified
by substrate specificity
- collagenases (MMP1)
- gelatinases (MMP2)
- stromelysins (MMP3)
72
Protease expression in cancer
penetration of basement membrane requires degradation of collagenase 4
- collagenase 4 is produced more in metastatic cells
- MMP3 is used for collagen 4 degradation
73
Which hormones are expressed at each stage of breast development
puberty
- estrogen
- ductal elongation
sexual maturation
- progesterone and estrogen
- ductal branching and budding
pregnancy and post-partum lactation
- prolactin and oxytocin
- expansion and differentiation
74
Examples of benign breast cancers
- fibroadenoma
| - lobular or ductal hyperplasia
75
examples of malignant breast cancers
- invasive lobular carcinoma (ILC)
| - invasive ductal carcinoma (IDC)
76
BREAST CANCER
Luminal A subtype identifiers (+-)
hormone receptor positive
HER2 negative
low Ki-67 (cell prolif)
77
BREAST CANCER
Luminal B subtype identifiers (+ +/-)
Hormone receptor positive
HER2 pos/neg
high Ki67
78
BREAST CANCER
Triple negative/basal-like subtype identifiers (--)
hormone receptor negative
| HER2 negative
79
BREAST CANCER
HER2 enriched subtype identifiers (-+)
Hormone receptor negative
| HER2 positive
80
BREAST CANCER
Normal like subtype identifiers (+-)
Hormone receptor positive
| HER2 negative
81
Traditional cancer treatments
surgery
chemo
radiation
82
Systemic cancer treatment
angiogenesis inhibitors
immunotherapy
83
Targeted cancer treatments
hormone therapy
monoclonal antibodies
84
How does chemotherapy work and what are its effects
nonspecific intracellular poisons which interfere with cell division
effects:
- damage to normal cells which divide rapidly (bone marrow, digestive tract, hair follicles)
85
What is radiation therapy and what are its effects
ionising radiation
- leads to formation of free radicals
damages DNA
- oxygen radicals
86
What are the characteristics of the environment inside a tumour?
Low blood supply therefore deficient in O2 = hypoxic environment
87
How can the the environment of the tumour be used for treatment advantage
hypoxia activated pro-drugs which only have effect in low oxygen environments
e.g evofosfamide (creates DNA crosslinks)
88
What is the relationship between treatment and the tumour environment
tumour hypoxia contributes to treatment failure and relapse
| - can lead to an aggressive phenotype which is resistant to both chemotherapy and radiotherapy
89
CANCER TREATMENT
the drug Avastin is approved for which tumours?
glioblastoma and colorectal tumours
90
CANCER TREATMENT
How does the drug Avastin function?
1. uses recombinant human monoclonal antibodies which inhibits vascular endothelial growth factor A
2. this blocks angiogenesis leading to lack of blood supply for the tumour
91
CANCER TREATMENT
What are the adverse effects of the drug Avastin?
bleeding
pulmonary embolism
92
BREAST CANCER TREATMENT
What are the 3 drug examples used in breast cancer?
Tamoxifen (TAM)
Fulvestrant (E17)
Herceptin
93
BREAST CANCER TREATMENT
How does Tamoxifen (TAM) work?
blocks estrogen receptor (ER) activity by acting like an estrogen molecule
- antagonist
94
BREAST CANCER TREATMENT
How does Fulvestrant (E17) work?
Binds to estrigen receptor (ER)
- down regulates ER by a functional blockage
under SERD class (selective ER degrader)
95
BREAST CANCER TREATMENT
How does Herceptin work?
antibody based drug to treat HER2 pos breast cancer
binds to domain 4 of extracellular segment of HER2 receptor (EGF receptor)
