CASE 7 Flashcards
1
Q
what changes occur as cancer develops?
A
increased number of cells:
- increased cell division
- cell survival/immortalisation
- cell growth
2
Q
describe the G0 cell cycle stage
A
where cells differentiate — most cells are in this stage. some cells can leave and re enter this stage (cells that are lost cannot be replaced)
3
Q
describe G1 and G2 phases of the cell cycle
A
cell grows — produces extra organelles to split between daughter cells
4
Q
what happens in S phase of the cell cycle
A
DNA replication
5
Q
when does cyclin B expression peak?
A
in mitosis
6
Q
what does cyclin B associate with and why?
A
cyclin B first associates with cyclin dependent kinase 1 (CDK1) to activate CDK1
7
Q
what is the role of CDK1?
A
the kinase is present throughout the cell cycle, it phosphorylates other proteins but ONLY when it is i a complex with cyclin B which is present in the transition form G2 to mitosis
8
Q
what does the CDK1 - cyclin B complex do?
A
the CDK1 activates and phosphorylates other proteins eg. Histone 1 (chromosome condensation), ,MAP (spindle formation), lamin (nuclear envelope breakdown) — all seen as cells exit G2 and go into prophase
9
Q
what is the cyclin D/CDK4 complex required for?
A
progression of G0 to G1
10
Q
what is the cyclin E/CDK2 complex required for?
A
progression from G1 to S phase
11
Q
what is the cyclin A/CDK2 complex required for?
A
sustain interphase so all DNA is replicated
12
Q
what is the cyclin A/CDK1 complex required for?
A
also plays role in progression of G2 to mitosis like the cyclin B/CDK1 complex
13
Q
what is necrosis?
A
accidental cell death due to injury which releases cellular contents leading to an inflammatory response when the spilled out cellular contents come into contact with neighbouring cells
14
Q
what is apoptosis?
A
the organised destruction of a cell which is initiated by either a signal from a neighbouring cell or the cell itself due to sensed internal damage. this process does not cause an inflammatory response and is common to referred to as programmed cell death.
15
Q
why is there no inflammatory response in apoptosis?
A
always in a vesicle surrounded by a membrane
16
Q
describe the process of apoptosis
A
- chromosomes will condense inside the cell
- fragmentation of the nucleus
- breakdown of cytoskeleton causing the cell to round up and start to bleb and release vesicles containing the cellular contents surrounded by a membrane — never released into surrounding environment
- these vesicles are phagocytosed by neighbouring cells and the contents are broken down into the basic amino acids, lipids, carbs, and nucleic acids for recycling in the neighbouring cell
17
Q
what is TNFa?
A
= tumour necrosis factor a (alpha)
18
Q
what does TNFa do?
A
binds to receptors on neighbouring cells, causing those receptors to trimerise — forms a trimer (3 receptor molecules), allows recruitment of intracellular proteins to make a signalling complex on intracellular side = DISC (death induced signalling complex)
19
Q
what does disc activate?
A
(death induced signalling complex) activates a series of proteases
20
Q
what do caspases do? what is inevitable once they are activated?
A
they degrade proteins in cell to cause to lead to cell death — apoptosis is inevitable once they are activated
21
Q
what is bax and what does it do when stimulated by intracellular signals?
A
it is a apoptosis regulator — intracellular signals cause Bax to relocate from cytoplasm to outer membrane of mitochondria— forms a pore in membrane — allows a release of proteins found within the intermembranous space between the outer membrane and inner membrane of mitochondria
22
Q
what do the released proteins from the mitochondrial intermembranous space do?
A
activate caspases — APOPTOSIS
23
Q
what is myc? result of decreasing its function?
A
= a protein which controls cell growth
reducing myc function decreases cell size
24
Q
mutations in what leads to tumour development?
A
proto-oncogenes and tumour suppressor genes
25
what do proto-oncogenes do?
promote cell division, survival and growth, cell proliferation
26
does a mutation in proto-oncogenes increase or decrease function? what kind of mutation?
protein function increased by mutation. DOMINANT mutation
27
what is the name of an activated proto-oncogene?
oncogene
28
give examples of a proto-oncogene in breast cancer
- ER (estrogen receptor)
| - HER2
29
what do tumour suppressor genes do?
inhibit progression through cell cycle — promote apoptosis and inhibit cell growth
30
does a mutation in a tumour suppressor gene increase or decrease protein function? what kind of mutation?
protein function is reduced by mutation — RECESSIVE mutation
31
list examples of tumour suppressor genes
- BRCA1
| - p53
32
what is worse, the loss of TSG or the activation of oncogenes?
the loss of tumour suppressor genes is worse
33
what is HER2?
= Human Epidermal Growth Factor 2
| - HER2 gene encodes a plasma membrane protein which acts as a receptor for EGF = epidermal growth factor
34
in the presence of EGF, what does HER2 do?
Her2 dimerises with a 2nd plasma protein called Her1 — recruits a complex from cytoplasm (Grb2 + Sos)
35
what does Sos do?
activates another protein attached to plasma membrane = ras
36
what does ras do?
ras signals (through a cascade of kinases) to cause the phosphorylation of a transcription factor ETS — allows it to associate and bind to DNA and promote transcription of the target gene
ras — raf — mek — erk — ets (phosphorylated)
37
why is EGF important in breast epithelium?
it is a very important signal within breast epithelium to promote cell proliferation to replace the ductal epithelium and the epithelium of the alveoli in the breast
38
over expression of HER2 in mammary epithelial cells cannot cause tumour formation in the absence of what?
cyclin D1 (plays a central role in the regulation of proliferation, linking the extracellular signaling environment to cell cycle progression)
39
is HER2 positive breast cancer hereditary?
no, unlike BRCA1/2 — it is a somatic mutation
40
test for Her2?
IMMUNOCYTOCHEMISTRY — uses antibodies that target specific peptides or protein antigens. these bound antibodies can then be detected using several different methods. biopsy taken to obtain tissue sample - tested to see if the cells have HER2 on their surface
41
BRCA1 is located on what chromosome?
chromosome 17
42
germline vs. somatic mutation
a germline mutation is inherited so is therefore present i every cell in your body. a somatic mutation is acquired later in life, causing damage to a gene in one cell at a time
43
BRCA1/2 mutation is what type of inheritance?
autosomal dominant
44
what does BRCA1 gene normally do?
normally synthesises protein called breast cancer type 1 susceptibility protein — responsible for DNA repair. this function is lost if mutated
45
what is SNP?
= single nucleotide polymorphism
not a mutation which truncates and stops the protein functioning, but rather a slight alteration in the protien — protein still manufactured
46
list environmental risk factors linked to breast cancer
1. overweight — 9% increases risk
2. alcohol — 6% increases risk
3. physical inactivity — 5% increases risk
4. smoking — 4% increases risk
5. suboptimal diet — 3% increases risk
47
list hormonal factors linked to breast cancer
1. breast feeding — decreases risk
2. lower age at 1st child — decreases risk
3. early menarche — increase risk
4. late menopause — increases risk
5. contraceptive pill — increases risk
6. combined HRT — increases risk
48
name 3 drugs which have been approved as a cancer preventative in women with a higher risk of breast cancer
1. TAMOXIFEN (premenopausal) — 40% reduced risk
2. TAMOXIFEN RALOXIFENE (postmenopausal) — 40% reduced risk
3. AROMATASE INHIBITORS (postmenopausal) — 50% reduced risk
49
what percentage of women testing positive for BRCA1/2 mutation choose to have bilateral risk-reducing mastectomy despite not having cancer?
about 50%
50
what is neoplasia?
= the process by which a neoplasm is formed
— cells divide more than they should
— cells die less than they should
51
what is tumour classification based on?
- behaviour: benign vs malignant
- site
- histological
- histogenesis: cell of origin
- aetiological: inheritance vs environmental
52
3 benign epithelial tumours
1. adenoma = benign neoplastic proliferation of secretory or glandular tissue
2. papilloma = benign neoplastic proliferation of non-secretory, non-glandular tissue
3. polyp = a mass attached to a surface, which may or may not be a neoplasm
53
3 malignant tumour names
1. cancer = any malignant tumour
2. carcinoma = a malignant tumour of epithelial tissue
3. sarcoma = a malignant tumour of stromal tissue
54
what are mesenchymal tumours named according to?
named according to the cell type, with a suffix
— oma = if benign
— sarcoma = if malignant
55
what are epithelial tumours named according to?
named according to the cell type
56
behaviour of benign vs malignant tumours
- a benign tumour grows by expansion, displacing adjacent tissue
- a malignant tumour grows by infiltration of local tissues and spreads to other parts of the body
57
primary vs. secondary malignant tumours
```
primary = original malignant tumour
secondary = remote “offspring” of a primary malignant tumour (aka METASTASIS)
```
58
name 5 routes of metastasis
1. lymphatics
2. blood
3. transcoelomic
4. along epithelial-lined spaces
5. within epithelium
59
what is tumour grading?
- how bad the tumour looks
- an assessment of the degree of differentiation of a tumour
- correlates with how aggressive it behaves
- only for malignant tumours
60
what is tumour staging?
- how far the tumour has got
- based on: size of primary tumour, extent of lymph node disease, any blood-bourne metastasis
- aka TNM = tumour node metastasis
- better prediction of outcome than grade
- criteria different for each tumour
61
list some effects of benign tumours
- mechanical pressure
- obstruction
- ulceration
- hormone production
- infection
- malignant change
62
list some effects of malignant tumours
- all the physical effects of benign tumours
- tissue destruction
- haemorrhage
- secondary infection
- cachexia
- pain
- anaemia (haemorrhage, bone marrow replacement, haemolysis)
- paraneoplastic syndromes
63
what is cachexia?
severe weight loss, increased metabolic rate
64
symptoms of breast cancer
- lump
- lumpiness
- nipple discharge/change
- skin changes
- pain
65
what is the 2 week rule?
every woman with a breast cancer lump is entitled to be seen in a breast clinic within 2 weeks
66
what is triple assessment of breast cancer?
every lump must be triple assessed before diagnosing/excluding breast cancer
1. clinical examination
2. imaging
3. biopsy
67
what are some indications for mastectomy?
1. multifocality
2. local recurrence
3. large tumour in small breast
4. BRCA gene mutation
5. extensive pre-cancer changes
6. previous radiotherapy for lymphoma (as young adult)
7. inflammatory breast cancer
8. personal preference
68
role of MDT in breast cancer?
EVERY breast cancer must be discussed by a whole MDT team and not one individual doctor
69
what is tamoxifen?
- selective estrogen receptor modulators, SERMs, selectively stimulate or inhibit the estrogen receptors — tamoxifen is a SERM
- blocks the action of estrogen (an antagonist) in breast tissue by binding to the estrogen receptors — prevents estrogen molecules from binding to it
- therefore no change in the shape of the receptor — coactivators cannot bind to it — no transcription
70
what is herceptin?
- it is a monoclonal antibody that binds to HER2
- prevents dimerisation, thus preventing the activation pathways leading to cell proliferation and cell survival
- it is a form of targeted therapy
- also used as adjuvant therapy, after surgery
71
what is a lumpectomy?
- breast conservation therapy
- removal of a breast lump, together with the surrounding tissue
- followed by radiotherapy treatment to the remaining breast tissue
- the operation removes the least amount of breast tissue, but leaves a small scar and sometimes a small dent in the breast
72
what is a mastectomy? radical vs. modified radical mastectomy?
- removal of entire breast tissue due to size of tumour
- radical mastectomy = removal of entire breast tissue, pectoralis major and minor and lymph modes
- modified radial mastectomy = removal of entire breast tissue, pectoralis minor and lymph nodes
73
what is a mastectomy sometimes followed by?
reconstruction surgery — corrects the anatomical defect and to restore form and breast surgery. involves the use of prostheses (implants), autogenous tissue transfers, or a combination of both
74
what is axillary node clearance?
removal of some (sentinel node) or all the lymph nodes in the axilla to check for malignancy
75
radiotherapy in breast cancer?
- given to the conserved breast after wide local excision to reduce local recurrence and to the chest wall after mastectomy
- the ionising radiation damages the DNA of the exposed tissue, leading to cell death
- to avoid healthy cells being affected, shaped radiation beams are aimed from several angles of exposure providing a larger absorbed dose their than in the surrounding healthy tissue
76
chemotherapy in breast cancer?
- use of anti-cancer (cytotoxic) drugs to destroy malignant cells
- the aim is to do the maximum damage to cancer cells while causing minimum damage to healthy tissue
- often administered as adjuvant therapy, following surgery
77
what is a risk-reducing bilateral salpingooophorectomy?
- removal of the ovaries and fallopian tubes
- reduces the risk of ovarian and fallopian tube cancer
- women who are high-risk BRCA mutation carriers are at a substantially higher risk of developing breast cancer or ovarian cancer
78
what is prophylactic treatment?
treatment that is used to PREVENT a person from getting a condition or disease
79
what is a mammogram and what is its use in breast cancer?
- x-ray of the breast
- in early stages, they can highlight calcification within the breast tissue
- microcalcifications: tiny Ca deposits usually found in an area of breast where cells are being replaced more quickly than normal
- not usually due to cancer — but sometimes a cluster may be a sign of pre-cancerous changes or early breast cancer
80
what is a needle biopsy?
insertion of a needle to extract tissue from targeted area
81
what is a needle biopsy used to differentiate?
differentiates non-invasive cancers from invasive cancers
82
what is DCIS?
= ductal carcinoma in situ
- NON-INVASIVE breast cancer
- cells inside these ducts have started to become malignant
- these cells are all contained inside the ducts and have not started spreading into the surrounding breast tissue — little chance of metastasis into lymph nodes
- in invasive ductal breast cancer, the cells have broken out of the ducts and spread into the surrounding breast tissue — there is then a chance that the cells can spread into lymph nodes
83
familial cancers
- 1% of all cancers
- single gene mutations (Mendelian disorders)
- most are inherited as autosomal dominant traits
- most due to inherited mutations of tumour suppressor genes
- inherited mutated gene increases cancer susceptibility
- eg. BRCA1 gene — predisposition to breast and ovarian cancer
84
sporadic cancer
- 99% of all cancers
- result of exposure to carcinogenic agents and unrepaired DNA replication errors
- results in somatic activation/inactivation of cancer genes
85
familial vs sporadic cancers
- F = early onset, S = late onset
- F = multiple tumours of the same type, S = single tumour usually
- F = other types of tumours, S = no other tumours usually
- F + S = tumour cells: both copies of TSG inactivated
- F = all other cells: one copy of tumour suppressor genes inactivated, S = all other cells: normal
86
what is triple negative breast cancer?
= a kind of breast cancer that does not have any of the receptors that are commonly found in breast cancer: ER, PR, HER2 receptor
- fewer targets for treatment
- often patients first need a lumpectomy or mastectomy, followed by chemotherapy or radiotherapy
87
what are estrogen receptors?
- found inside the nucleus of cells, activated by estrogen
| - when estrogen binds to its complementary receptor, the receptor changes shape
88
what does the estrogen-receptor complex do?
it binds to specific DNA sites called estrogen response elements, which are located near genes that are controlled by estrogen
- binds to coactivator proteins and more nearby genes become active
89
what is the effect of estrogen in hepatocytes?
increases the amount of HDL cholesterol and decreases the amount of LDL cholesterol — helps lower the risk of heart disease
90
what is the effect of estrogen in breast cells?
- estrogen causes CELL PROLIFERATION of the cells lining the milk glands — thereby prepares the breast to produce milk if the woman should become pregnant. when estrogen levels deplete at the end of the menstrual cycle, these cells deteriorate and die
91
what is the effect of estrogen in bones?
regulate bone formation (osteoblasts) and bone resorption (osteoclasts) and epiphyseal plate closure
92
what is the effect of estrogen in the uterus?
growth of endometrium in menstrual cycle
93
progesterone receptors
- found in the cytoplasm of cells
- when no binding hormone is present the carbonyl terminal inhibits transcription
- when progesterone binds to the receptor, there is a structural change that removes the inhibitory action
- after progesterone binds, restructuring with dimerisation follows and the complex enters the nucleus and binds to DNA
- transcription takes place, resulting in formation of mRNA that is translated by ribosomes to produce specific proteins
94
what is the definition of metaplasia?
the change in the type of adult cells in a tissue to a form abnormal for that tissue
95
a cancer that has spread from the breast to the lung is known as what?
metastatic breast cancer
96
list 3 tumour suppressor genes
1. APC
2. BRCA1
3. p53
97
what is the function of retinoblastoma protein?
acts as a brake in the advancement of cells from G1 to S phase
98
how common is a BRCA in breast cancer?
5-10%
99
what name is given to a malignant tumour arising from goblet cells in the colon?
adenocarcinoma
100
tumour grade refers to what?
how well differentiated cells of the tumour are compared to the cells of origin
101
how do gatekeeper cells function to prevent malignancy from occurring?
regulate cell proliferation and death via apoptosis
102
death due to brain tumours is likely because of what?
pressure to organs
103
what is a treatment specific to breast cancers which are ER+?
tamoxifen
104
what is the suffix of a cancer of the supporting tissues?
sarcoma
105
what does T3 N2 M0 mean? (TNM staging)
a large tumour which has spread to 2 lymph nodes and has not metastasised distally
106
dermatitis is an infection of what layer of the skin?
papillary layer
107
where do the biceps brachii long head muscles insert?
tuberosity of radius
108
what do natural killer cells (NKC) secrete large amounts of?
IFN-y and TNF-a
109
what is progression through the cell cycle regulated by?
cyclin/CDK complexes
110
what are the 6 capabilities of a cancer?
a successful cancer must:
1. become independent of external growth signals
2. become insensitive to external anti-growth signals
3. become able to avoid apoptosis
4. become capable of indefinite replication
5. become capable of sustained angiogenesis
6. become capable of tissue invasion and metastasis
111
what do common cancers usually show?
genomic instability — either chromosomal instability (bizarre karyotype, structural/numerical abnormalities) or micro satellite instability (high frequency of sequence errors after DNA replication)
112
in oncogenes, how many copies of the gene needs to be activated?
one copy
113
in tumour suppressor genes, how many copies of the gene needs to be inactivated?
both copies of the gene need to be inactived
114
if breast cancer spreads from the super lateral quadrant of the breast, what are the first lymph nodes most likely to be affected?
anterior axillary (pectoral) nodes
115
what is a normal gene that regulates cell proliferation but can promote a cancerous phenotype when mutated?
proto-oncogene
116
what is the most common malignant tumour of the female breast?
adenocarcinoma
117
what is carcinoma in situ best defined as?
full thickness epithelial abnormality (dysplasia) without microinvasion
118
DNA damage to double strand DNA breaks is caused primarily by what?
ionising radiation
119
how does tamoxifen inhibit the spread of breast cancer cells?
acting as a ligand analogue of oestrogen
