Cancer Flashcards

Question

What are the three germ cell layers?

Answer 1

1. ectoderm 2. mesoderm 3. endoderm

Answer 2

- males = almost always malignant - females = alsmost always benign

Answer 3

- most are benign, but there is a risk of malignancy - localised overgrowth of cells and tissues native to the organ - cells are mature but architecturally abnormal - common in children and should stop growing when they stop - e.g. bile duct hamartomas, bronchial hamartomas

Answer 4

- Nottingham scoring system

Answer 5

- cells with poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to each other and to endothelial cells -\> very bad tumours

Answer 6

- the degree of differentiation -\> higher grade = poor differentiation

Answer 7

- how far a tumoru has spead -\> higher stage = greater spread

Answer 8

- if a cell is quiescent, it is NOT proliferating – this is the G0 phase - cells can be STIMULATED to enter the cell cycle: G1 -\> S phase -\> G2 -\> MITOSIS - there are checkpoints within the cell cycle -\> they arrest the cell in the cycle, to check everything is okay

Answer 9

- code for proteins involved in maintenance of cell growth, division and differentiation

Answer 10

- can be converted into oncogenes -\> protein products of oncogenes don't respond to control influences - oncogenes can be be perversely expressed, over-expressed or perversely active e.g. MYC, RAS, ERB, SIS

Answer 11

- mutation in the coding sequence - gene amplification - chromosomal translocation -\> leading to chiamaeric genes - insertional mutagenesis -\> viral infection

Answer 12

- the picture is of a Philadelphia chromosome -\> translocation of segements from chromosome 9 and 22 - two key areas that are translocated are: ABL on chromosome 9 and BCR on chromosome 22 -\> results in BCR-ABL fusion gene -\> development of cancer (CML)

Answer 13

- upon binding GTP, Ras becomes active -\> when bound to GTP, it is active so it interacts with a protein called RAF and signals via phosphorylation - it activates the kinase cascade leading to the production of gene regulatory proteins - RAS passes the signal on to other proteins within a signal transduction cascade -\> the cell goes into a PROLIFERATIVE PHASE - dephoshorylation of the GTP to GDP to switch Ras off o when RAS in on it signals to the kinase cascade -\> drives recruitment of effector proteins

Answer 14

- mutant Ras will fail to dephosphorylate GTP, meaning that the GTP persists so Ras remains active -\> consequently INCREASED SIGNALLING with the RAF protein -\> continuous proliferative stimulation

Answer 15

- a signal transduction cascade called the Mitogenic-activated Protein Kinase (MAPK) Cascade - MORE SPECIFICALLY THE EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) CASCADE -\> specfic to growth stimulatory signalling

Answer 16

- only one, the other copy will be insufficient to stop its effects

Answer 17

- growth factors - growth factor receptors - intracellular transducers (signalling proteins) - intracellular receptors - transcription factors - cell cycle regulatory proteins - cell death regulators

Answer 18

- regulate cell proliferation and maintain cell integrity (essential activities in the cell) - typical proteins whose function is to regulate cellular proliferation and maintain cell integrity

Answer 19

- both = two hit hypothesis - an exception is p53because the mutated gene become dominant

Answer 20

- family history of related cancers - unusually early onset – the mutation often only affects ONE COPY -\> usually of the a tumour suppressor gene - bilateral tumours in paired organs - synchronous or successive tumours - tumours in different organ systems in same individual - mutation inherited through the germline

Answer 21

- is a malignant cancer of developing retinal cells - sporadic disease usually involves one eye - hereditary causes can be unilateral or bilateral and multifocal

Answer 22

- caused by mutation of the RB1 tumour suppressor gene on chromosome 13 - RB1 encodes a nuclear protein that is involved in regulation of the cell cycle

Answer 23

- removal of th eye - if it is inherited the tumour will be present at birth or shortly afterwards -\> only eye with tumour is removed even though it is likely the other eye will develop the tumour too

Answer 24

- metabolic homeostais - anti-oxidant defence - DNA repair - growth arrest - senescence - apoptosis in worst case

Answer 25

- stress or DNA damage causes p53 to be released from Mdm2

Answer 26

- cell adhesion and signalling -\> involved in WNT pathway -\> binds to beta-catenin and inhibits its drive for proliferation

Answer 27

- hyperproliferative state of colonic cells -\> polps of the colon will appear -\> THIS IS NOT CANCER - 90% risk of developing colorectal carcinoma

Answer 28

- removal of their colons in their 20s

Answer 29

- embryonic cells vs adult cells -\> embryonic divide at a much faster rate - complexity of systems/organism -\> a less complex system will divide more rapidly - necessity for renewal -\> in the body, certain cell types must divide more rapidly to replenish lost cells -\> intestinal epithelial cells are shed very often so need quick replenishment (20 hours) but hepatocytes don’t need frequent renewal (1 year) - state of differentiation -\> some cells NEVER divide -\>neurones and cardiac myocytes

Answer 30

- anti-cancer mechanism which works by promoting pro-liferation in cells which are not in contact with other cells but stopping growth when they do come into contact with one another - lost in cancer cells

Answer 31

- during mitosis

Answer 32

- mitosis is a complex process, it must to occur very quickly due to cell vulnerability - cells are more easily killed during mitosis (manipulated clinically: irradiation, heat shock, chemicals) -\> principal of treating tumours - DNA damage occurring during mitosis cannot be repaired -\> mutation may be carried over in DNA - gene transcription is silenced - is a slow down in the metabolism of the cells

Answer 33

o replication for division - DNA replication - protein synthesis -\> initiation of translational proteins, and elongation is increased - capacity for translation is also increased - replication of organelles -\> with mitochondria, cells needs to co-ordinate with replication of mitochondrial DNA

Answer 34

- consists of two centrioles (barrels of 9 triplet microtubules) - there are matrix proteins holding the centrioles at 90 degree angles to each other - is a mother and daughter centriole

Answer 35

- microtubule organising centre (MTOC) -\> controls the polymerisation of microtubules - co-ordinate the mitotic spindle

Answer 36

- prophase - prometaphase - metaphase - anaphase - telophase - cytokinesis

Answer 37

- condensation of chromatin

Answer 38

- double helices are wrapped around histones to forms 'beads-on-a-string' form of chromatin - compact the chromatin from being 2 nm wide to 11 nm wide - string is then further wrapped around itself to form 30 nm fibres - 30 nm fibres are then extended as a scaffold forming a chromosome scaffold of 300 nm - then further wrapped until you end up with a chromosome

Answer 39

- a complex of proteins that are a key regulator of the processes around chromosomes in the cell cycle - surround the centromere of chromosomes

Answer 40

- microtubules are radiating away from the centrosome - the nuclear envelope is breaking down and by doing so, the chromosomes come out into the cytoplasm and migrate to opposite sides - begin to organise the spindle

Answer 41

- radial microtubule arrays - polar microtubules

Answer 42

- fibres formed around each centrosome -\> as soon as the nucleus starts to break down, they start to form around the MTOC - come out of the MTOC at all angles

Answer 43

- when two radial arrays from two centrosomes meet in the middle they are referred to as polar microtubules

Answer 44

- breakdown of nuclear membrane is finalised - spindle formation is largely complete - attachment of chromosomes to spindle via kinetochores

Answer 45

- microtubule from opposite pole is captured by sister kinetochore -\> chromosomes attached to each pole congress to the middle via the microtubules

Answer 46

- CENP-E is a centromere protein E (kinetochore tension sensing) -\> senses whether the kinetochore is attached to microtubules or not

Answer 47

- the point/stage at which chromosomes have aligned at the equator of the spindle fibres

Answer 48

- paired chromatids separate to form 2 daughter chromosomes - can be split into anaphase A and anaphase B

Answer 49

- a protein complex that holds the sister chromatids tightly bound together -\> acts as a glue

Answer 50

- cohesin is broken down and the microtubules get shorter -\> daughter chromatids start moving towards opposite spindle poles

Answer 51

o daughter chromosomes can reach the opposite poles by two motions: - shortening of the microtubules that form the spindles - pulling apart of the spindle poles (spindle poles migrate apart) o once chromosmes have reached the poles of the spindles the cell enters telophase

Answer 52

- daughter chromosomes arrive at the pole - nuclear envelope reassembles at each pole - is a condensation of material where the cells are going to split - assembly of a contractile ring of actin and myosin filaments -\> squeezes the cell so that it divides into 2 daughter cells -\> the cleavage furrow is where the cells are going to be cleaved

Answer 53

- when the cells divide, they usually round up - once the cells divide, we see the remaining component where the cells were once joined -\> this is the mid-body - with time, a new membrane will be inserted here and the cells will become completely separated from each other

Answer 54

- kinetochore has proteins that emit a signal when the kinetochore is not attached to microtubules -\> once the kinetochore attaches to microtubules, it stops emitting the signal - are many proteins involved in this signalling process but two important ones are: CENP-E and BUB Protein Kinase

Answer 55

- BUBs dissociate from the kinetochore when chromatids are properly attached to the spindle -\> when all dissociated, they go on to signal progression to anaphase

Answer 56

- normal attachment of kinetochore -\> the microtubule array of one centrosome is attached to the kinetochore of one sister chromatid, and the microtubule array of another centrosome is attached to the kinetochore of the other chromatid

Answer 57

- both the kinetochores are hooked by two microtubule arrays from the SAME centrosome -\> one cell having a duplication, and the other having one chromosome less

Answer 58

- more than one microtubule array attached to the same kinetochore -\> means that one of the chromatids is being pulled in two different directions -\> both sister cells will be missing that chromosome

Answer 59

- only one of the kinetochores of one chromatid is attached to a microtubule array, the other kinetochore is unattached -\> on esister cell will lose a chromosome

Answer 60

- mis-attachment of microtubules to kinetochores - aberrant centrosome - aberrant DNA duplication

Answer 61

- if centrosome duplication is defective there may be a situation in which you end up with 4 centrosomes -\> can lead to very abnormal attachment of the microtubule arrays to the kinetochores leading to abnormal cytokinesis -\> result is 4 daughter cells

Answer 62

- if DNA is over-replicated (usually doubled) -\> end up with aberrant cytokinesis, where there are two normal daughter cells, two cells with a single chromosome, and one cell without ANY chromosome

Answer 63

- activation of this kinase holds cells in G" until everything is ready -\> inhibition of this means cells rush into mitosis -\> will be a lack of chromosomes or organelles so the cell will die

Answer 64

- alter microtubule dynamics -\> produce unattached kinetochores -\> causes long-term mitotic arrest

Answer 65

- breast - ovarian

Answer 66

- cell cycle arrest -\> usually happens at the checkpoints -\> may be due to the detection of DNA damage -\> can be temporary/can be resolved by repair - apoptosis -\> if something is very wrong in the cell: DNA damage is too great and cannot be repaired, chromosomal abnormalities or toxic agents

Answer 67

- 1^st checkpoint is during G1 - 2^nd is just before mitosis -\> checks for DNA damage before entering mitosis (G2) - 3^rd is a metaphase-anaphase checkpoint

Answer 68

- exploit the first checkpoint by hyper-activating growth factors -\> tumour cells over-express growth factors -\> result is induction of cells to overcome this checkpoint - tumours can also block the DNA damage machinery, inducing cells to enter mitosis when they shouldn’t - block exit from the cell cycle into G0

Answer 69

- response to extracellular factors - signal amplification - signal integration - modulation by other pathways - regulation of divergent responses

Answer 70

- epidermal growth factor (EGF) - platelet derived growth factor (PDGF)

Answer 71

- when the dimeric ligand binds, it induces dimerization of the monomeric receptors -\> this is the SIGNALLING UNIT - dimerization activates the kinase domain - there is cross-phosphorylation of receptors due to kinase domains being brought close together - phosphorylated amino acid residues in the kinase domain -\> ACTIVATION -\> phosphorylation of proteins in the tail of the EGF receptor

Answer 72

- first kinase is activated by phosphorylation (ligand binds to tryosine kinase type receptor which acts via a small GTP-binding protein called Ras) -\> further kinases are activated by the activated kinases and so on…

Answer 73

- a transcription factor - controls the expression of other genes - is a proto-oncogene -\> overly expressed in a lot of tumours

Answer 74

- regulation of enzyme activity by protein phosphorylation (kinases) - adapter proteins - regulation by GTP-binding proteins

Answer 75

- an antibody that inhibits HER2 receptor tryosine kinase - important in a number of tumours including breast cancer where is it overly expressed

Answer 76

- anti-HER2 antibodies -\> blocks the early stages of growth stimulation

Answer 77

- adapter proteins are modular containing many domains -\> different domains are mixed and matched to give the protein different properties, and are important in molecular recognition -\> some domains are important in molecular recognition - have no enzymatic function of their own, simply bring other proteins together

Answer 78

- an important adaptor molecule in growth factor signalling -\> an exchange factor for RAS - has 2 types of protein-protein interactions: - \> SH2 - binds to the phosphorylated tyrosines of the receptor - \> SH3 (2 copies): bind to the proline-rich regions of other proteins -\> always bound to it through Sos

Answer 79

- V12Ras -\> glycine residue in position 12 of Ras protein is changed to valine - L61Ras -\> glutamine in position 61 in converted to leucine

Answer 80

- side chain goes from being a simple hydrogen (glycine) to a hydrophobic side chain (valine) - prevents GAPs from binding to Ras -\> Ras can't turn off very easily -\> constantly stimulating division

Answer 81

- side chain goes from being an amide to a hydrophobic side chain - inhibits the intrinsic GTPase activity of the Ras protein -\> Ras ends up constantly being in the GTP bounds (on) state and therefore giving growth stimulatory signals

Answer 82

- Raf - B-Raf is a common mutation in melanomas -\> can be be inhibited for a while until the tumour takes over

Answer 83

- once phosphorylated, the transcription factors go on to regulate gene expression - one of the most important genes that is activated by this pathway is the c-Myc gene -\> Myc and Ras are key molecules in stimulating growth

Answer 84

- cyclin -\> once they have actived the CDKs they are degraded (higher concentration during mitosis) - different CDK-cyclin interactions activates/controls different stages of the cell cycle - regulated further by cyclins and phosphorylation

Answer 85

- a family of kinases -\> are serine-threonine kinases - are in the cell throughout the cell cycle but they are not activated until they bind to an activating protein called cyclin - CDKs are present in proliferating cells throughout the cycle, but the levels vary. -\> are involved in controlling the process

Answer 86

- binds to cyclin B to phophorylate substrates at mitosis -\> breaks down the nuclear envelope

Answer 87

- binds to cyclin E -\> active kinase will be phosphorylated at the start of synthesis - a tumour suppressor that is inactivated in many cancers

Answer 88

- cyclin binds to CDK -\> activates phosphorylation by CDK activating kinase - this is followed by Cdc25 removing the inhibitory function from the kinase Wee1 by removing the phospahe -\> Wee1 provides inhibition from entering mitosis to early - after this you get ACTIVE MPF

Answer 89

- when active at the end of metaphase MPF phosphorylates a number of key substrates that are involved in the mitotic process -\> puts mitosis on hold when the substrates are phosphorylated - once the kinetochores are correctly attached to the microtubule spindles, a signal is released that causes cyclin B to be degraded/inactivated -\> substrates which were keeping mitosis on hold are dephosphorylated so then mitosis can progress

Answer 90

- GDK2 and cyclin E

Answer 91

- CDK2 and cyclin E - CDK2 and cyclin A

Answer 92

- CDK1 and cyclin B

Answer 93

- cyclins activate CDKs AND alter substrate specificity -\> the same CDK is being used in G1/S phase and S phase but they are doing different jobs

Answer 94

- a key protein in regualting the cell cycle -\> is present throughout the cell cycle o IS A TUMOUR SUPPRESSOR GENE

Answer 95

- in the resting G0 state, retinoblastoma is unphosphorylated -\> it binds to and sequesters a family of transcription factors called E2F -\> E2F TFs are held in the cytoplasm by unphosphorylated retinoblastoma -\> EVRYTHING IS TURNED OFF - retinoblastoma is a target for CDK4/6-cyclin D kinase -\> kinase phosphorylates the retinoblastoma protein -\> once phosphorylated, it loses its affinity for E2F so it releases E2F -\> E2F TFs can then bind to promoters in the nucleus of genes involved in cell cycle progression

Answer 96

- c-Myc induction

Answer 97

- cyclin E -\> next cyclin required for cell cycle progression

Answer 98

o INK4 family is active in G1 -\> inhibit CDK4/6 by displacing cyclin D o CIP/KIP family is active in S phase -\> inhibit ALL the CDK/cyclin complexes by binding to them

Answer 99

o CARCINOGENS: o chemicals -\> dietary (40-45% of all human cancer is associated with diet), lifestyle, environmental, occupational, medical, endogenous (e.g. mitochondria produce oxygen radicals which may damage DNA) o radiation -\> ionizing, solar, cosmic

Answer 100

- base dimers and chemical cross-links - base hydroxylations - abasic sites - single strand breaks - double strand breaks - DNA adducts and alkylation

Answer 101

- where DNA molecules are chemically linked up

Answer 102

- during the repair process, the entire DNA base has been removed so the sugar backbone is maintained but the base from the mutagenic molecule has been removed

Answer 103

- general type of damage caused by chemicals - some chemicals tend to be metabolically activated into electrophiles -\> DNA is very rich in electrons because of all the nitrogens in the bases -\> electrophiles covalently bind to the DNA - binding of a big bulky chemical to the DNA causes problems particularly during replication because the DNA polymerase runs along the strand figuring out which base to put next, but ican't if it is bound to a big chemical group

Answer 104

o polycyclic aromatic hydrocarbons - common environmental pollutants, formed from combustion of fossil feusl and tobacco

Answer 105

o two-step epoxidation 1. oxidised by CYP450, to produce an epoxide/oxide -\> is reactive and unstable (potentially dangerous) -\> is an electrophile 2. epoxide hydrolase metabolises this molecule, to form a dihydrodiol which is harmless. 3. the non-toxic dihydrodiol metabolite is also a substrate for P450 -\> converts this non-toxic metabolite into another oxide (DIOL EPOXIDE) -\> is INCREDIBLY reactive (even more so than the previous reactive oxide) and NOT STABLE AT ALL

Answer 106

- the product of it metabolism (a diol epoxide) is a very unstable electrophile -\> BIGGEST SOURCE OF ELECTRONS in the cell is DNA -\> DNA is adducted -\> starts mutation process

Answer 107

- a very potent human liver carcinogen formed by aspergillus flavus mould - common on poorly stored grains/peanuts -\> especially common in Africa and Far-East

Answer 108

- aflatoxin B1 is oxidised by P450 -\> aflatoxin B1-2,3-epoxide (VERY REACTIVE) -\> reacts with the N7-position of guanine to form big, bulky, chemical DNA adducts -\> DNA in the cell is now read as damaged - when the DNA is fixed, it’s fixed inappropriately, and a mutation has been introduced into the DNA

Answer 109

- a potent bladder carcinogen - used to be used in dye industry but it is now very uncommon to come into contact with it

Answer 110

- 2-naphthylamine is a substrate for CYP450, which converts the amino group to form a hydroxylamine -\> hydroxylamines are reactive but are glucuronidated (detoxified) in the liver by glucuronyl transferase - inactive metabolite is excreted by the liver and it goes into the bladder and mixes with the urine -\> urine is ACIDIC, and, under acidic conditions, the glucuronides are hydrolysed -\> in the acidic conditions, the molecule rearranges to form a positively charged nitrogen (nitrenium ion) - nitrenium ion is an electrophile, which then goes and binds to the DNA and forms adducts -\> the bladder isn't as capable of detoxifying the hydroxylamine derivative as the liver so can lead to mutations

Answer 111

o UV radiation can lead to the formation of pyrimidine dimers - if 2 pyrimidines are next to each other, in the presence of UV radiation, they can covalently link -\> cell tries to repair this, but in doing so, a mutation is introduced

Answer 112

- cause the formation of oxygen free radicals -\> very potent electrophiles - usually either super oxide radicals or hydroxyl radicals

Answer 113

o double (DAMAGING) and single strand (not a big deal) breaks -\> double stranded breaks have to be re-annealed and rebuilt, which can introduce mutations o generate apurinic and apyrimidic sites -\> base stripped out of the DNA o introduced are base modifications: -\> ring-opened guanine + adenine, thymine + cytosine glycols (2 hydroxy groups on the molecule) or 8-hydroxyadenine + 8-hydroxyguanine (particularly mutagenic)

Answer 114

c. cytochrome P450

Answer 115

o general stress on the cell, includes: - oxidative stress, nitric oxide, hypoxia, ribonucleotide depletion, mitotic apparatus dysfunction, oncogene activation, DNA replication stress, double-stranded break, telomere erosion

Answer 116

- a tumour suppressor gene that actiuvates many pathways - mild physiological stress e.g. DNA repair or growth arrest = p53 orchestrating a transcriptional series of events and activates proteins that help repair the problem - SEVERE stress = p53 activating an apoptotic pathway by interacting with apoptosis proteins

Answer 117

1. direct reversal of DNA damage 2. base excision repair 3. nucleotide excision repair 4. during or post replication repair

Answer 118

- photolyase splits cyclobutane pyrimidine-dimers formed from UV light to recover the pyrimidines - methyltransferases and alkyltransferases remove alkyl groups from DNA bases

Answer 119

1. DNA glycosylase split/hydrolyses between the sugar and the DNA base 2. AP-endonuclease splits the DNA strand so there is a gap in the S-P backbone 3. DNA polymerase fills in the missing base (determines correct base using complementary strand) 4. DNA Ligase then seals the DNA to form intact DNA - mainly for apurinic/apyrimidinic damage

Answer 120

1. endonuclease makes two cuts in the DNA on either side of the site of damage -\> patches can be long (100-200 nucleotides) or short (~10-20 nucleotides) 2. helicase will then remove this patch, leaving the double stranded DNA with a patch missing 3. DNA Polymerase replaces the removed bases using the complementary strand as a template 4. DNA Ligase then joins the DNA up again o process is energy-demanding and requires a lot of proteins - mainly for bulky DNA adducts

Answer 121

d. base excision repair

Answer 122

- guanine and the adenine - are the most electron-rich molecules -\> most susceptible to electrophile damage

Answer 123

- term used to describe the way cells interact with their external environment and their reactions to this, particularly proliferative and motile responses of cells

Answer 124

- chemical influences: hormones, growth factors, ion concentrations, ECM (density, composition), molecules on other cells, nutrients and dissolved gas (O2/CO2) concentrations - physical influences: mechanical stresses, temperature, the topography or “layout” of the ECM and other cells (the organisation of the ECM)

Answer 125

- growth factors - cell-cell adhesion - cell-ECM adhesion

Answer 126

- cell require to be bound to an extracellular matrix to be reactive to soluble growth factors and therefore proliferate

Answer 127

- attachment to the ECM may be reuired for cell survival

Answer 128

- cells have receptors on their cell surface which bind specifically to ECM molecules -\> often link at their cytoplasmic domains to the cytoskeleton - this arrangement means that there is mechanical continuity between ECM and the cell interior

Answer 129

- one of the groups of cell-ECM adhesion complexes -\> MST IMPORTANT ECM RECEPTORS - are heterodimer complexes of a and b subunits that associate extracellularly by their “head” regions -\> each of the “leg” regions spans the plasma membrane - ligand-binding (attachment to the ECM) occurs at the junction of the head regions

Answer 130

- bind specifically to short peptide sequences on ECM proteins - for example a5b1 fibronectin receptor binds to arg-gly-asp (RGD) - RDG is found on multiple ECM molecules -\> fibronectin, vitronectin, fibrinogne plus others

Answer 131

- binds to arg-gly-asp (RGD)

Answer 132

- a6b4 integrin complex found in epithelial hemidesmosomes are linked to the cytokeratin

Answer 133

- ECM receptors (e.g. integrins) can act to transduce signals -\> ECM binding to an integrin complex can stimulate the complex to produce a signal inside the cell

Answer 134

o a molecule outside the cell stimulates a signal inside the cell -\> this is “outside-in” integrin signalling - the cell binds to the matrix via the integrin -\> stimulates an intracellular signal - the composition of the ECM will determine which integrin complexes bind and which signals it receives -\> can alter the phenotype of the cell -\> not all cells express the same integrins

Answer 135

- alpha and beta heterodimers don't have enzymatic activity in themselves -\> cannot signal directly -\> however, they can recruit other molecules, some of which are signalling molecules and molecules that associate with the actin cytoskeleton

Answer 136

- a cell can stimulate the cell to generate an internal signal -\> a signal generated inside the cell (e.g. as the result of hormone binding to receptor) can act on an integrin complex to alter the affinity of an integrin

Answer 137

- inflammation or blood clotting - switching on adhesion of circulating leukocytes

Answer 138

- competition for growth factor occurs -\> the hihger the density the greater the growth factor -\> slower metabolism and division

Answer 139

- growth factor - ECM -\> anchorage dependence o both activate the same pathways (e.g. MAPK) -\> individually they are weak and/or transient but together they strong and sustained

Answer 140

- most non-epithelial cells “collide”, they do not form stable cell-cell contacts -\> actually “repel” one another by paralysing motility at the contact site -\> promotes the formation of a motile front at another site, and moving off in the opposite direction -\> this is contact inhibition of locomotion - is responsible for preventing multi-layering of cells in culture and in vivo

Answer 141

- mutual induction of spreading to create a stable monolayer - total spread of contacted cells is greater than that of non-contacted

Answer 142

- when there are NO cell-cell junctions, MAPK is activated, p27KIP1 is decreased -\> HIGH PROLIFERATION - if calcium is added, junctions re-form à inactive MAPK, p27KIP1 is increased à LOW PROLIFERATION

Answer 143

- cadherin is a calcium-dependent, homophilic cell adhesion molecule -\> its cytoplasmic tail is associated with BETA-CATENIN which is in turn associated to ALPHA-CATENIN and the actin cytoskeleton

Answer 144

- when bound to cadherin at the membrane, beta-catenin not available for LEF-1 binding and nuclear effects -\> must become unbound to have its nuclear upregulation -\> is tightly regulated - normally, cytoplasmic beta-catenin rapidly degraded - if beta-catenin cytoplasmic levels rise as a result of inhibition of degradation or loss of cadherin-mediated adhesion, beta-catenin/LEF-1 complex enters nucleus and influences gene expression -\> proliferation -\> possible cancer

Answer 145

- clustering of cadherins after cell-cell contact is known to alter the activation of small GTPases -\> e.g. Rac is activated, Rho is inhibited -\> influences proliferation - some growth factor receptors are associated with cell-cell junctions -\> reduces their capacity to promote proliferation

Answer 146

- proliferate uncontrollably (lose density dependence of proliferation) - less adherent and will multilayer (lose contact inhibition of locomotion and anchorage dependence) - epithelia breakdown cell-cell contacts - not Hayflick limited -\> become immortalised -\> cancer

Answer 147

- allows the invasion of cells -\> won't be inhibited by the contact

Answer 148

- cell-cell adhesion must be down-regulated (e.g. cadherin levels reduced) - cells must be motile - degradation of ECM must take place; matrix metalloproteinase (MMP) levels increased in order to migrate through basal lamina and interstitial ECM

Answer 149

- embryonic development - wound healing - menstraul cycle

Answer 150

- baldness - ischaemia -\> MI, stroke - limb fractures - thrombosis

Answer 151

- angiodysplasia -\> HHT and VWD - cerebral malformations -\> AVM/CCM

Answer 152

- retinal disease - cancers - atherosclerosis - obesity

Answer 153

o vasculogenesis -\> bone marrow progenitor cell, usually during development -\> involves progenitors that form a blood vessel from scratch o angiogenesis -\> sprouting (most common in adults and involved in disease processes) -\> vessels sprout from a PRE-EXISTING blood vessel o arteriogenesis -\> collateral growth (mechanism through which collaterals are formed) -\> collaterals may bypass a blockage.

Answer 154

1. there is a need for new blood vessels -\> usually the result of hypoxia 2. growth factors are released that activate endothelial cells in the pre-existing capillaries 3. endothelial cells undergo a conformational change -\> go from being part of a very organised monolayer, to sending out filopodia 4. endothelial cells begin to migrate towards the growth factors -\> to allow the endothelial cell to do this, the cytoskeleton of the tip cell must be modified and it needs to control the interaction with neighbouring cells at cell-cell junctions 5. tip cells will keep on moving until they find another tip cell, with which they will fuse -\> tip cells themselves do not divide -\> require their neighbouring cells to divide behind them to push the tip cells towards the GF 6. eventually, the tip cell will meet another tip cell and it will fuse and stabilise

Answer 155

- VEGFs - FGFs - PDGFB - EGF - LPA

Answer 156

- thrombospondin-1 - the statins -\> angiostatin, endostatin, canstatin, tumstatin

Answer 157

- under normal conditions, HIF is inhibited by Von Hippel-Lindau (tumour suppressor gene) -\> as HIF is inhibited, it doesn't drive the expression of angiogenesis genes - in hypoxia Von Hippel-Lindau does NOT bind to HIF -\> HIF is mobilised and can translocate into the nucleus and drive the expression of genes involved in angiogenesis -\> one major target of HIF is the expression of VEGF (vascular endothelial growth factor)

Answer 158

- VEGF-A - VEGF-B - VEGF-C - VEGF-D - PIGF (placental GF)

Answer 159

- 3 tryosine kinase receptors called VEGFR1, VEGFR2 and VEGFR3 - the receptors can combine to form dimers

Answer 160

- neuropilin-1 (Nrp1) - neuropilin-2 (Nrp2)

Answer 161

- VEGFR-2 is the major mediator of VEGF-dependent angiogenesis - activates signalling pathways that regulate endothelial cell migration, survival and proliferation

Answer 162

- at first the vessel is quiescent -\> endothelial cells are some of the SLOWEST DIVIDING CELLS IN THE BODY - in angiogenesis, the cells exit quiescence and proliferate rapidly -\> VEGF is one of the most important triggers for this transformation from quiescent cells via tip cells - lots of other things must happen simultaneously -\> one cell is a tip cell, the other cells must divide -\> this complex process happens by NOTCH SIGNALLING o is not specific to endothelial cells -\> example is for angiogenesis

Answer 163

1. binding of the notch ligand (DII4) to the notch receptor activates it by cleaving the intracellular domain (NICD) 2. NICD translocates to the nucleus where it binds to the TF RBP-J and regulates transcription 3. a tip cell is chosen -\> it begins to express notch ligand which binds to the stalk cells' notch receptors 4. stalk cells then begin to divide and push the tip cell towards the growth factor

Answer 164

1. in stable blood vessels, Dll4 and Notch signalling maintain quiescence 2. VEGF activation increases expression of Dll4 3. Dll4 drives Notch signalling, which inhibits expression of VEGFR2 in the adjacent cell 4. Dll4-expressing tip cells acquire a motile, invasive and sprouting phenotype 5. adjacent cells (Stalk cells) form the base of the emerging sprout, and proliferate to support sprout elongation

Answer 165

- once the tip cell and stalk cells have been identified, the sprout needs to progress forwards -\> cells will interact with the ECM and there will be guidance systems in place - macrophages also have an important role in vessel anastomosis (both physiological and pathological) -\> carve out tunnels in the ECM, providing avenues for subsequent capillary infiltration

Answer 166

- macrophages appear to help stabilise newly formed vessels (by promoting tip cell fusion) - once the tip cells have fused and the stalk cells are separating to form a patent tube, the new vessel needs to stabilise - stabilisation involves reforming the endothelial monolayer barrier and recruiting neural cells (PERICYTES) and switching off the active angiogenesis process

Answer 167

- constitutively expressed at junctions - mediates adhesion between endothelial cells - controls contact inhibition of cell growth - promotes survival of EC

Answer 168

o angiopoietin-tie2 system modulates the activation and return to quiescence of endothelial cells - angiopoietin 1, when bound to Tie2, promotes quiescence in the vasculature - angiopoietin 2 is released when new blood vessels are required, in respond to inflammation or when the vasculature needs to be destabilised o Ang-2 antagonises Ang-1 signalling and has pro-angiogenic effects

Answer 169

o there's a point at which the tumour gets to a certain size where diffusion is no longer sufficient, so some cells within the tumour become hypoxic and send angiogenic signals - tumours less than 1mm³ receive oxygen and nutrients by diffusion from host vasculature -\> tumours larger than this, they require new vessel networks - angiogenesis facilitates its progressive growth, migration, proliferation and further neovessel formation

Answer 170

- irregularly shaped, dilated, tortuous - not organised into definitive venules, arterioles and capillaries - leaky and haemorrhagic, partly due to the over-production of VEGF - perivascular cells often become loosely associated - some endothelial cells may recruit endothelial progenitor cells from the bone marrow

Answer 171

- normalise and stabilise tumour blood vessels to reduce hypoxia and improve efficiency of drug delivery to the tumour

Answer 172

o no -\> is reversed for very advanced cancers - avastin has limited efficacy and many side effects -\> side effects due to VEGF being essential for the homeostasis of the endothelium - no overall survival advantage over chemotherapy alone - no quality-of-life or survival advantage

Answer 173

GI perforation - hypertension - proteinuria - venous thrombosis - haemorrhage - wound healing complications

Answer 174

- an anti-VEGF humainsed MAb (mouse anitbody) -\> anti-angiogenesis drug - also called Bevacizumab

Answer 175

- tumour adopts an evasive strategy and adapts to bypass the specific angiogenic blockade - intrinsic or pre-existing difference -\> idea that a tumour was not very sensitive to VEGF in the firsat place -\> knocking out VEGF made little difference

Answer 176

- age-related macular degeneration -\> main cause of blindness

Answer 177

- ischaemic diseases

Answer 178

- surgery - chemotherapy - radiotherapy - immunotherapy o endocrine therapy is used in the treatment of some cancer -\> breast

Answer 179

- cytotoxic chemotherapy -\> kills cells - targeted therapies

Answer 180

- alkylating agents - antimetabolites - anthracyclines - vinca alkaloids and taxanes - topoisomerase inhibitors

Answer 181

- small molecule inhibitors - monoclonal antibodies

Answer 182

- target cells that are rapidly dividing in the body -\> mostly by attacking their DNA - does affect all rapidly dividing cells -\> lots of side effects -\> mouth ulceration, severe diarrhoea etc

Answer 183

- IV or oral

Answer 184

- add alkyl (C_NH_2N+1) groups to guanine residues in DNA -\> causes cross-linking (intra, inter, DNA-protein) of DNA strands - prevents DNA from uncoiling at replication - triggers apoptosis (via checkpoint pathway)

Answer 185

- can lead to secondary cancers such as leukaemia - benefits of this treatment outweigh the negatives

Answer 186

- chlorambucil - cyclophosphamide - dacarbazine - temozolomide

Answer 187

- like alkylating agents but instead of an alkyl group, these agents add platinum to guanine residues in DNA - causes cross-linking (intra, inter, DNA-protein) of DNA strands - prevents DNA from uncoiling at replication - triggers apoptosis (via checkpoint pathway)

Answer 188

- cisplatin - carboplatin - oxaliplatin

Answer 189

- cause hair loss (not carboplatin) - nausea - vomiting - diarrhoea - immunosuppression - tiredness - nephrotoxicity - neurotoxicity - ototoxicity (toxic to the ear) (platinums)

Answer 190

- agents are purine, pyrimidine or folate analogues - are incorporated into the DNA -\> inhibition of DNA synthesis -\> DNA double strand breaks - at the DNA checkpoint, the cell recognises this as an error -\> apoptosis

Answer 191

- methotrexate (folate) - 6-mercaptopurine - decarbazine and fludarabine (purine) - 5-fluorouracil - capecitabine - gemcitabine (pyrimidine)

Answer 192

- hair loss (alopecia) -\> not 5FU or capecitabine - bone marrow suppression -\> causes anaemia, neutropenia and thrombocytopenia -\> increased risk of neutropenic sepsis (and death) or bleeding - nausea and vomiting (dehydration) - mucositis and diarrhoea - palmar-plantar erythrodysesthesia (PPE) - fatigue

Answer 193

- inhibit transcription and replication by intercalating nucleotides within the DNA/RNA strand - also block DNA repair, so can be mutagenic - create free oxygen radicals -\> damages cell membranes and DNA

Answer 194

- doxorubicin - epirubicin

Answer 195

- cardiac toxicity -\> cause arrythmias and heart failure in particular -\> probably due to damage induced by free radicals - alopecia - neutropenia - nausea and vomiting - fatigue - skin changes - red urine (doxorubicin “the red devil”)

Answer 196

- vinca alkaloids = inhibit assembly of mitotic microtubules - taxanes = inhibit dissembly of mitotic microtubules o both cause dividing cells to undergo mitotic arrest

Answer 197

- nerve damage -\> peripheral neuropathy, autonomic neuropathy - hair loss - nausea - vomiting - bone marrow suppression -\> neutropenia, anaemia thrombocytopenia - arthralgia -\> pain in joints - allergy

Answer 198

- topoisomerases are required to prevent DNA torsional strain during DNA replication and transcription - induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA -\> this protects the free ends of DNA from aberrant recombination events - blocking this enzyme prevent protection to the free ends of DNA

Answer 199

- acute cholinergic type syndrome - diarrhoea, abdominal cramps and diaphoresis (sweating) -\> therefore given with atropine - hair loss - nausea, vomiting - fatigue - bone marrow suppression -\> neutropenia, anaemia, thrombocytopenia

Answer 200

- in an attemot to minimalise the diarrhoea, abdominal cramps and sweating

Answer 201

- DNA repair mechanisms may be up-regulated to repair damage caused by chemotherapeutic agents -\> DNA double strands WON’T break -\> cell survival - DNA adducts may be replaced by base excision repair (using PARP) - drugs may be effluxed from the cell by ATP-binding cassette (ABC) transporters

Answer 202

1. self–sufficient 2. insensitive to anti-growth signals -\> survivals with minimal stimulation and grows regardless of intake 3. anti-apoptotic 4. pro-invasive and metastatic -\> spreads rapidly into the surrounding area 5. pro-angiogenic 6. non-senescent 7. dysregulated metabolism 8. evades the immune system 9. unstable DNA 10. inflammation

Answer 203

- monoclonal antibodies target the extracellular domain of the receptor, and NEUTRALISE the ligand -\> antibody therefore prevents dimerization of the receptor - cause the receptor to be internalised, into the cell - also activate Fcγ-receptor-dependent phagocytosis - cytolysis induces complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity

Answer 204

- bevacizumab binds and neutralises VEGF -\> improves survival in colorectal cancer - cetuximab targets EGFR -\> also used in colorectal cancers

Answer 205

- small molecule inhibitors bind to the kinase domain of the tyrosine kinase within the cytoplasm - block auto-phosphorylation and downstream signalling

Answer 206

- GLIVEC (imatinib) - targets bcr-abl protein specifically -\> this protein drove the over-production of WBCs in CML

Answer 207

- mutations in ATP-binding domain (e.g. BCR-Abl fusion gene targeted by Glivec) - intrinsic resistance (herceptin effective in 85% HER2+ breast cancers, suggesting other driving pathways) - intragenic mutations - upregulation of downstream or parallel pathways

Answer 208

- single stranded, chemically modified DNA-like molecules of 17-22 nucleotides in length o complementary nucleic acid hybridisation to target gene hindering translation of specific mRNA -\> recruits RNase H to cleave target mRNA - good for “undruggable” targets -\> haven't really been used in practice yet

Answer 209

- harmful cells -\> e.g. cells with viral infection or DNA damage - developmentally defective cells -\> e.g. B lymphocytes expressing antibodies against self-antigens - excess/unnecessary cells -\> embryonic development -\> brain to eliminate excess neurons; liver regeneration; sculpting of digits and organs - obsolete organs -\> e.g. mammary epithelium at the end of lactation - exploitation -\> chemotherapeutic killing of cells

Answer 210

- necrosis -\> unregulated cell death associated with trauma, cellular disruption and an INFLAMMATORY RESPONSE -\> no ATP required - apoptosis -\> regulated, controlled disassembly of cellular contents without disruption -\> NO INFLAMMATORY RESPONSE -\> requires ATP

Answer 211

- plasma membrane becomes permeable -\> cell swelling and rupture of cellular membranes -\> release of proteases leading to auto-digestion and dissolution of the cell (unregulated action) - localised inflammation occur due to the attraction of immune cells - associated with trauma -\> mechanical, chemical, bacteria etc

Answer 212

o latent phase = death pathways are activated, but cells appear morphologically the same o execution phase = orderly activation of specific proteins and kinases: - loss of microvilli and intercellular junctions - dramatic cell shrinkage - loss of plasma membrane asymmetry -\> phosphatidylserine lipid appears in outer leaflet - chromatin and nuclear condensation - DNA fragmentation - formation of membrane blebs - fragmentation into membrane-enclosed apoptotic bodies -\> because the contents aren’t released, there is no inflammation o apoptotic bodies are taken up by macrophages

Answer 213

- will form over the top of the dying cell to maintain the constant epithelial barrier

Answer 214

- apoptosis (PCD) -\> regulated cell death -\> controlled disassembly of cellular contents with no inflammatory response - apoptosis-like PCD -\> some, but not all, features of apoptosis -\> may be a display of phagocytic recognition molecules, even before plasma membrane lysis - necrosis-like PCD -\> variable features of apoptosis before cell lysis -\> “aborted apoptosis” can occur up to a certain point down the process - necrosis -\> unregulated cell death associated with cellular disruption and an inflammatory response o NECROSIS AND APOPTOSIS CAN BE INTER-LINKED -\> cell death is a SPECTRUM

Answer 215

1. the executioners -\> caspases (key enzymes) 2. initiating the death programme -\> via death receptors (extrinsic) and/or mitochondria (intrinsic) 3. the Bcl-2 family 4. stopping the death programme

Answer 216

o initiator and effector - initiator caspases are the first to be triggered (2, 9, 10 and 8) -\> contains specific motifs (e.g. CARD for 2 and 9, DED for 10 and 8) - effector caspases (3, 6 and 7) don’t contain these motifs

Answer 217

- pro-caspases (zymogens) are single chain polypeptides - to become activated, they must undergo proteolytic cleavage to form large and small subunits -\> initiator caspases must also be cleaved to release the targeting subunit - these cleavages are done by the caspases themselves - after the cleavage, you get folding of 2 large and 2 small chains to form an active L2S2 heterotetramer

Answer 218

- amplification - divergent responses - regulation o inititaor caspases cleave and activate effector caspases

Answer 219

- cleaving and inactivating various proteins and complexes -\> e.g. nuclear lamins leading nuclear breakdown - activating enzymes by direct cleavage or cleavage of inhibitor molecules -\> e.g. protein kinases or nucleases such as Caspase-activated DNAse (CAD)

Answer 220

- death by design -\> receptor-mediated (extrinsic) pathways - death by default -\> mitochondrial (intrinsic) death pathway

Answer 221

- all cells have death receptors on their surface consisting of: - extracellular cysteine-rich domain - single transcellular domain - cytoplasmic tail (with a death domain)

Answer 222

- encounter secreted or transmembrane trimeric ligands (e.g. TNF-alpha or Fas) -\> these are called DEATH LIGANDS

Answer 223

- when activate death receptors (such as Fas) attract FADD adaptor protein - the DD domain on FADD binds to the DD domain of the intracellular section of the receptor - the DED domain of the FADD can then bind to the DED domain of pro-caspase-8 to form a death-inducing signalling complex (DISC) -\> bring pro-caspase within close proximity allows cleavage to release active initiator caspase 8 tetramer -\> you need at least 2 pro-caspase to form an active tetramer

Answer 224

- when inactivate death receptors (such as Fas) attracts FLIP adaptor protein - the DD domain on FADD binds to the DD domain of the intracellular section of the receptor - the DED domain of the FADD can then bind to the DED domain of FLIP -\> prevents the activation of pro-caspase-8

Answer 225

o to regulate apoptosis - FADD = activation of cell death - FLIP = inhibition of cell death

Answer 226

- an initiator caspase -\> activates caspase 3 and 7

Answer 227

- is the intrinsic pathway whereby cellular stresses cause a loss of mitochondrial membrane potential (essential to cell life) - \> results in the release of cytochrome C and other apopotosis-inducing factors - \> stimulate the formation of an apoptosome complex

Answer 228

- consists of an APAF-1 central ring as well as terminals where cytochrome C, ATP and pro-caspase 9 can bind - APAF-1 is an ATPase protein -\> at the C-terminus, it has WD-40 repeats - 7 APAF-1 monomers form 1 APAF-1 heptamer

Answer 229

- can potentially bind a pro-caspase 9 -\> oligomerisation brings multiple pro-caspase 9s close together, resulting in cleavage, activation and release as active caspase 9 tetramer -\> initiates a caspase cascade leading to apoptosis

Answer 230

- Bid links the receptor-mediated and mitochondrial death pathways -\> once one pathway is triggered the other one will be triggered too - caspase 8 from the receptor-mediated pathway can cleave Bid -\> enhances release of mitochondrial proteins, thus engaging the intrinsic pathway -\> Bid promotes the release of cytochrome C from the mitochondrion, which triggers the mitochondrial death pathway

Answer 231

- Bid - Bad - Bax - Bak o move between cytosol and mitochondria

Answer 232

- Bcl-2 - Bcl-xL o localised to the mitochondrial membrane

Answer 233

- GF receptors that dimerise -\> causes phosphorylation of a tyrosine site on the cytoplasmic tail -\> attracts an adaptor -\> adaptor recruits PI3 kinase, which contains 2 subunits: p85 and p110 - phosphatidylinositol 3-kinase (PI3-K) is a lipid kinase involved in growth control and cell survival - three main subunits: targeting subunit, adapter subunit and catalytic subunit - it phosphorylates PIP2 into PIP3, which is recognised by the adapter subunit of PKB/Akt (protein kinase B) -\> PKB/Akt is an anti-apoptotic enzyme

Answer 234

- phosphorylates and inactivates Bad (key regulator of apoptosis) - phosphorylates and inactivates caspase 9 - inactivates FOXO transcription factors -\> FOXOs promote expression of apoptosis-promoting genes - stimulates ribosome production and protein synthesis

Answer 235

o distinct and sequential events - normally, hyper-proliferation leads to a BULK of cells (solid tumour) -\> cells still have some contact with each other, and are bound to each other within the tissue - as soon as the cells de-differentiate, they break away from the basement membrane (no longer in contact) -\> metastatic tumour cells can invade veins and exit at different sites in the body - once tumour cells exit the venous/lymphatic systems, they can COLONISE and METASTASISE at long distances from the site of origin

Answer 236

- individual -\> single cell migration - collective -\> group of cells

Answer 237

- lymphoma - leukaemia - SCLC

Answer 238

- fibrosarcoma - glioblastoma - anaplastic tumours

Answer 239

- epithelial cancers - melanoma

Answer 240

- epithelial cancers - vascular tumours

Answer 241

o morphogenetic events - for example -\> breast-feeding - when tissue has to grow, cells bud to grow and branch in order to form the mammary glands -\> whole tissue will invade its surroundings and grow around

Answer 242

- normal = sense spaces between them -\> immediately, migrate together to close the gap -\> is how healing works, uses COLLECTIVE MIGRATION - cancer = sense spaces between them -\> immediately migrate, however it is unorganised -\> cells migrate everywhere -\> becomes invasive as contact inhibition is ineffective in cancer cells

Answer 243

- organogenesis and morphogenesis - wounding - growth factors/chemoattractants - de-differentiation (tumours)

Answer 244

- directionality (polarity) of movement that is essential - become larger in the direction that they are moving

Answer 245

- focal adhension - lamellae - filopodia

Answer 246

- contact-inhibition motility

Answer 247

- CANNOT migrate by the standard processes - focal adhesions hook onto the ECM matrix, and grab it to provide points where the cells can attach -\> engage their cytoskeleton to connect -\> this is used so that TRACTION FORCES ARE GENERATED

Answer 248

- finger-like protrusions that are enriched with actin filaments - sense the environment and tell the cell where to should attach -\> used to co-ordinate their movement

Answer 249

- sheet-like, structure that expands, protrusions rich in actin filaments - cell migrates in a certain direction, and the sheets of membrane project to the front of the cell -\> sheets then ruffle back, so that the cell can move

Answer 250

- motility = the movement of a cell in space - cell movement = change in cell shape which makes movement possible

Answer 251

o hapoptatic motlity = directional motility or outgrowth of cells with no purpose o chemotactic motility = movement in response to a chemical stimulus -\> is a purposeful response - both have the same core machinery

Answer 252

- similar to us rock-climbing

Answer 253

- signal reaches the cell, and is recognised -\> is a rapid disassembly of the filaments -\> rapid diffusion of monomers of actin -\> reassembly at the side of the cell that is going towards the source -\> repolarisation of cell

Answer 254

o filapodium = actin is in its filamentous form, in a parallel arrangement -\> bundle together to provide structure to the membranous filopodia projection o stress fibres = perpendicular filament organisation -\> required to make contractions -\> during contraction actin filaments slide along each other to shorten their distance -\> contracts the cell body -\> end at the focal adhesions o lamellipodia = no direct fibres, but there are branched and cross-linked fibres (like a net) that provide support to the big sheet of membrane

Answer 255

- nucleation step is the rate-limiting step in the organisation of the cytoskeleton into F-actin - requires a lot of energy - Arp = actin-related proteins have a similar structures to actin \> help monomers to form a trimer -\> once this step happens, filaments can form - Arp-2,3 complex binds to the minus end of the actin filament to form the initial trimer, and extend the filament

Answer 256

o after trimer formation, elongation must occur (extension of the filament) -\> free actin monomers bind to the positive end o different classes of proteins assists the process: - profilin is a protein that binds to G-actin (monomeric actin), and drags it over to the actin filament - thymosin protein binds to actin monomers and inhibits the polymerisation process (act like a brake)

Answer 257

- capping proteins regulate the elongation process of the filament -\> capping protein binds the end of the filament and prevent monomers from being added on - filaments are very dynamic -\> once adding is blocked, there is a disassembly process -\> results in shortening of the filament

Answer 258

- filament size can be regulated by severing -\> unsevered actin filament grows and shrinks -\> severing proteins chop the filament up, which counter-intuitively generates more ends so that filaments can grow more rapidly

Answer 259

+ end = Cap Z, gelsolin, fragmin/severin - end = tropomodulin, Arp complex

Answer 260

- gelsolin - ADF/cofilin - fragmin/severin

Answer 261

- nucleation - elongation - capping - serving

Answer 262

- fascin will bind filaments together at a particular distance - fimbrin will also bind filaments together, but between those at a long distance from one another - alpha-actinin is a dimer, which binds filaments - spectrin, filamin and dystrophin will cross-link the filaments in particular angles. -\> each particular protein will make a specific angle with the filaments

Answer 263

- dystrophin

Answer 264

- in the lamella actin has a very precise angle of 70 degrees in the filaments - Arp-2 complex is the protein responsible for the branching appearance of the filaments as the cells move forward in the lamellar -\> allows nucleation to occur and filaments to elongate outwards

Answer 265

- when cells needs to move and project, the rigid cell cortex must be broken -\> this is called gel-sol transition - gel is a rigid structure of the actin cytoskeleton -\> cross-linking proteins hold the filaments as a mesh - if the membrane pushes through, this gel mesh must be broken down, severing does this -\> actin cross-linking proteins are still present, but the filaments aren’t forming a mesh anymore -\> allows a sol that can flow/cytoplasm can move to another area

Answer 266

- hypertension - Wiskott-Aldrich Syndrome -\> immunodeficiency, eczema, autoimmunity - Duchenne Muscular Dystrophy (muscle wasting) - Bullous Pemphigoid (autoimmune disease)

Answer 267

- Alzheimer

Answer 268

- at the back of the lamella, there is SEVERING, so that you can release the assembly of the filament -\> allows the G-monomers to move to the point in the cell (at the front), where they are needed to make new assemblies - lots of co-ordination between these activities -\> net result is new assembly of actin at the leading edge (provided by monomers at the back of the cell, that have been generated to move the cell)

Answer 269

- tight filaments with bundling proteins -\> form by complexes that stimulate the bundling and polymerisation of the filaments - then they form a bundle, and elongate by adding monomers (one at a time), and pushing the membrane in a localised position - as a result, there is a very fast elongation from the cell -\> when the filopodia senses the removal of the stimulus, it collapses -\> done by bring capping proteins, to stop the process and erode the base -\> the membrane is pushed down.

Answer 270

- ion flux changes -\> e.g. intracellular calcium levels can affect proteins - phosphoinositide signalling -\> e.g. phospholipid binding - kinases/phosphatases (phosphorylation cytoskeletal proteins) - signalling cascades via small GTPases -\> master regulators

Answer 271

- a subfamily of 20 small GTPases belongs to the Ras super-family - levels are often upregulated in cancers

Answer 272

- are activated by receptor tryosine kinase which cause hydrolysis of GTP -\> GDP which regulates activity - once activated, small G proteins bind to specific proteins (known as effectors) -\> effectors are the messengers that carry out actions

Answer 273

- Cdc42= induces filopodia - Rac = huge expansion and flattening of the cell - Rho = indcues stress fibres

Answer 274

- are due to oestrogen driving their growth -\> therapies can be designed against this

Answer 275

- carcinoma

Answer 276

- mammary gland is an important organ -\> primary function is to produce milk, to feed the young baby - is the only organ that develops post-natally -\> initially is present as a rudimentary gland -\> during puberty, when hormonal changes occur, these signals drive the growth and development of the mammary gland itself - subsequent to this, the gland can undergo further development, according to pregnancy and lactation cycles o mammary gland is a very fatty organ -\> the fatty stroma surrounds the breast network o imbedded in the fat is a ductal network of tubules and alveoli, which comes together at the nipple o any cell type in the mammary gland can give rise to tumours

Answer 277

- tube is hollow as it has to conduct milk -\> ring of 2 layers of epithelial cells lines the lumen -\> outermost layer is myoepithelial cells -\> are able to contract. - layer of myoepithelial cells, some of which are slightly vacuolated, make contact with the basement membrane - myoepithelial cells are important in the development of the tubular structures in the mammary gland - \> tumours can arise from the luminal (inner layer) epithelial cells -\> these luminal epithelial cells have receptors required to respond to steroid hormones (particularly oestrogen) -\> between 10-20% of luminal cells respond to oestrogen

Answer 278

o can be a local proliferation of cells that are LUMINAL -\> proliferate within the tubule, without breaking away from the tube -\> is no loss of the myoepithelial cells - is a benign condition called benign in situ carcinoma -\> are locally proliferating cells that may appear as a lump -\> easily diagnosed as non-cancer but it is a precursor state for the development of cancer o lobular carcinoma is where cancer cells try to form tube-like structures, but FAIL -\> is some indication that these cells retain the ability to behave like a normal luminal epithelial cell o medullary carcinoma looks nothing like breast cancer cells or epithelial cells -\> packed full of vesicles that are rich in neuro-endocrine peptides and hormones o vast majority of breast cancers have an intermediate organisation -\> involves no specialised structure, and just a growth of cells

Answer 279

- age of onset of menarche -\> if periods are early, oestrogen cycling begins early - age to first full-term pregnancy -\> early pregnancy is protective against breast cancer - some contraceptive pills - some hormone-replacement therapies

Answer 280

- nuclear receptor -\> when bound to oestrogen on the nucleus of a cell it becomes a transcription factor

Answer 281

- cell proliferation -\> can lead to cancer -\> cyclin D1, C-myc and TGF-alpha are commonly affected in breast cancers

Answer 282

- progesterone (nuclear receptor) - VERY strongly oestrogen-regulated gene in the mammary gland -\> if the progesterone receptor is being expressed, the oestrogen receptor is working/probably to much -\> convenient test to find out whether a tumour is oestrogen positive

Answer 283

- around 1/3 of premenopausal women with advanced breast cancer respond to oophorectomy - postmenopausal women responds to high-dose therapy with synthetic oestrogens -\> causes negative feedback mechanism takes place, and degradation of the receptor takes place -\> tumour cells no longer express the oestrogen receptor, so cannot be driven with oestrogen

Answer 284

- not well tolerated - resistance often follows remission -\> patients can get metastatic disease - drugs must be given in high dose (and have many side effects)

Answer 285

- surgery -\> from lumpectomy to full mastectomy

Answer 286

- surgery is the PRIMARY treatment -\> lumpectomy through to full mastectomy -\> often also the removal of sentinel lymph nodes - patients who undergo surgery are often given radiotherapy, chemotherapy or endocrine therapy prior to surgery, to shrink the tumour -\> neo-adjuvant therapy - mostly, endocrine treatment is given after surgery -\> this is adjuvant therapy

Answer 287

- ovarian suppression (in pre-menopausal women) - blocking oestrogen production by enzymatic inhibition - inhibiting oestrogen responses

Answer 288

- ovaries are the major source of oestrogen in pre-menopausal women - ovarian ablation aims to eliminate this source - can be achieved by: surgical oophorectomy, ovarian irradiation or pharmacologically

Answer 289

- major problems associated with these procedures are morbidity and irreversibility - many people undergoing this are denied the chance of having children (fertility is lost) - surgery or irradiation

Answer 290

- reversible and reliable medical ovarian ablation can be achieved using LHRH agonists - LHRH agonists bind to LHRH receptors in the pituitary -\> receptor down-regulation and suppression of LH release and inhibition of ovarian function, includes oestrogen production - when coming off the treatment, ovarian function and fertility is stored -\> can have children while they are being treated for breast cancer o LHRH agonists include “Goserelin”, “Buserelin”, “Leuprolide” and “Triptorelin”

Answer 291

- aromatase inhibitors - anti-oestrogens

Answer 292

- tamoxifen

Answer 293

- tamoxifen is a competitive inhibitor of oestradiol binding to the ER - anti-oestrogens negate the stimulatory effects of oestrogen by blocking the ER -\> causes the cell to be held at the G1 phase of the cell cycle - is the endocrine treatment of choice for metastatic disease in post-menopausal patients -\> 1/3 of patients respond to treatment - few side effects reported: hot flushes (29%) are experienced in some

Answer 294

o selective oestrogen receptor modulators (SERMs) - long-term administration of an anti-oestrogen has the potential to precipitate premature osteoporosis -\> however, tamoxifen has oestrogenic effects in bone -\> doesn’t block its function in the bone - long-term administration of an anti-oestrogen could produce a population at risk for premature CHD -\> however, tamoxifen has oestrogenic effects in the CVS

Answer 295

- increase in vasomotor symptoms - increased cataracts - increases thromboembolism - promotes endometrial cancer, fibroids, polyps and vaginal discharge

Answer 296

- despite reducing overal breast cancer incidence it does increase incidence of endometrial cancer, stroke, DVT and cataracts

Answer 297

- aromatase consists of a complex containing a cytochrome P450 heme containing protein and the flavoprotein NADPH cytochrome P450 reductase - aromatase catalyses three separate steroid hydroxylations involved in the conversion of androstenedione to oestrone - can metabolise androstenedione, which is produced by the adrenal glands -\> leads to the production of oestrone sulphate, which is circulated in the plasma o blocking aromatase = blocked oestrogen production

Answer 298

- aromatase inhibtors

Answer 299

- Type I -\> initially compete with the natural substrate for binding to the active site of the enzyme -\> enzyme specifically acts on the inhibitor to yield reactive alkylating species, which form covalent bonds at or near the active site of the enzyme -\> enzyme is irreversibly inactivated - Type II -\> bind reversibly to the active site of the enzyme and prevent product formation only as long as the inhibitor occupies the catalytic site

Answer 300

- progestins response in the breast is complex and influences proliferation and differentiation function -\> used in endocrine treatment of uterine and breast cancer with anti-neoplastic properties - over-stimulation of the progesterone receptor causes its down-regulation

Answer 301

- hard to treat once it is metastatic -\> significant propertion of patient present once in is metastatic - treatment is done in cycles of different strategies to attempt to cure but isn't very effective

Answer 302

- early age of onset of menarche - late age to menopause - age at first full-term pregnancy - some forms of the contraceptive pill - hormone Replacement Therapy - obesity -\> fat can convert androgens into oestrogen - diet, physical activity, height, medication (e.g. aspirin)

Answer 303

- extract water from faeces, and is therefore slightly involved in electrolyte balance - faecal reservoir (evolutionary advantage) - bacterial digestion of vitamins (e.g. vitamin B and K)

Answer 304

- enormous turnover -\> 2-5 million cells die per minute in the colon - proliferation renders cells very vulnerable -\> a problem with the genetics may result in cancer -\> APC mutation prevents cell loss -\> MUTATION - normally we have protective mechanisms to eliminate genetically defects -\> natural loss, DNA monitors, repair enzymes

Answer 305

- a projection from a mucosal surface into a hollow vicus

Answer 306

- very common and BENIGN (NOT dysplastic) - \<0.5 cm - 90% of all LI polyps - often multiple occuring in one individual - no malignant potential -\> DON'T CAUSE CANCER - 15% have k-ras mutation

Answer 307

- benign neoplasm of the mucosal epithelial cells – associated with increased cancer risk

Answer 308

- metaplastic/hyperplastic -\> completely benign and very common - adenomas -\> increase risk of cancer - juvenile - Peutz Jeghers - lipomas - others (essentially any circumscribed intramucosal lesions)

Answer 309

- tubular (\>75% tubular) – 90% - tubulovillous (25- 50% villous) – 10% - villous (\> 50% villous) - (flat and serrated) OR - pedunculated -\> like a tree where the mucosa is grass - sessile -\> like a rug on carpet - slightly raised but not too much

Answer 310

- columnar cells will have some nuclear enlargement, elongation, multi-layering and loss of polarity - increased proliferative activity - reduced differentiation - complexity/disorganisation of architecture

Answer 311

- mucinous cells with nuclear enlargement, elongation, multi-layering and loss of polarity - exophytic, frond-like extensions - sometimes have hyper-secretory function and result in excess mucus discharge and hypokalemia

Answer 312

o a disease in which people have THOUSANDS of polyps in the bowel - sufferers inevitably get cancer, unless the bowel is removed (many patients have prophylactic colectomy (\<30)) - APC is a familial condition (genetic mutation in 5q21 gene) - site of mutation determines clinical variants (classic, attenuated, Gardner, Turcot etc.)

Answer 313

o 25% of adults have adenomas before the age 50 o 5% of these become cancers if they are left alone -\> increased risk of cancer - large polyps have higher risk of cancer development than small ones (so 5% \> 1 cm 50-60, 15% at 75) - about 10-15 years between getting a polyp and getting cancer

Answer 314

- adenoma carcinoma sequence - microsatellite instability

Answer 315

- mutation in genes such as APC, K-ras, p53, telomerase activation occur - these increase your chance of polyps and adenomas therefore carcinoma o cumulative damage to the DNA -\> loss of control of cell growth -\> adenoma -\> carcinoma

Answer 316

- microsatellites are repeat sequences prone to misalignment -\> some are in coding sequences of genes which inhibit growth or apoptosis e.g.TGFbR11 - mismatch repair genes (MSH2, MLH1 + 4 others) = repair mistakes in the genetic code - if mismatch repair genes are damaged (microsatellite instability), DNA cannot be repaired - recessive genes so require 2 hits - HNPCC- germline mutation in these genes

Answer 317

- FAP = inactivation of APC tumour suppressor genes - HNPCC = microsatellite instability

Answer 318

- 50 to 80 - equal incidence in men and women - western diet

Answer 319

- high fat - low fibre - high red meat - refined carbohydrates

Answer 320

- folate -\> destroyed in over-cooking of food - vitamin C -\> scavenge free radicals - vitamin E -\> scavenge free radicals - cruciferoes vegetables - polyphenols -\> activate MAPK - garlic -\> associated iwth apoptosis - green tea -\> EGCG-induced telomerase activity

Answer 321

o classic triad: - CHANGE IN BOWEL HABIT - RECTAL BLEEDING -\> most commonly due to cancer of teh rectosigmoid or descending colon - UNEXPLAINED IRON DEFICIENCY ANAEMIA -\> blood is mixed in with faeces and therefore doesn't appear as bleeding - other symptoms = bloating, cramps and constitutional (weight loss, fatigue)

Answer 322

- carcinoma has a different distribution around the bowel -\> distribution is very similar to adenomas o caecum/ascending colon = 22% - transverse colon = 11% - descending colon = 6% - recto-sigmoid = 55%

Answer 323

- adenocarcinomas -\> derived from glands - are some sub-tupes of adenocarcinomas but these are rare -\> mucinous carcinoma, signet ring cell and neuroendocrine

Answer 324

- 10% well differentiated -\> looks like the glands it originally come from - 70% moderately differentiated -\> MOST CANCERS IN THE GI TRACT - 20% poorly differentiated

Answer 325

- lymph nodes which are situated partly posterior to the upper portion of nearby the pectoralis minor - only direct territorial afferents are those that accompany the cephalic vein, and one that drains the upper peripheral part of the mamma - THE MAJOR LYMPH NODES

Answer 326

- depends on the staging of the cancer - almost always includes surgery but can also include chemotherapy (more types of chemo for worse stage), metastatectomy and palliatve options

Answer 327

o high risk screening - previous adenoma - 1^st degree relative affected by colorectal cancer before the age of 45 - 2 affected first degree relatives - evidence of dominant familial cancer trait -\> colorectal, uterine, and other cancers - ulcerative colitis and Crohn’s disease (inflammation increases the risk of cancer) - hereditable cancer families (include other sites) o population screening

Answer 328

- 55 -\> send out a faecal test to see if there is any blood in the faeces - positives are referred for colonoscopy (60-75 years) or sigmoidoscopy (55-60 years)

Answer 329

- D - exclude the most serious issue first unless an obvious other causes (large piles) are present

Answer 330

- invasion and metastasis -\> are not abnormal behaviours for maematopoietic or lymphoid cells as their job is to travel around the body and enter tissues - chronic and acute are instead used as a marker of the severity of the cancer

Answer 331

- chronic = cancer with a 'benign' manner -\> disease will go on for a long time - acute = cancer with a 'malignant manner' -\> patient will die rapidly unless treatment occurs

Answer 332

- acute lymphoblastic leukaemia (ALL) - acute myeloid leukaemia (AML) - chronic lymphocytic leukaemia (CLL) - chronic myeloid leukaemia (CML)

Answer 333

- leukaemia results from a series of mutations in a single stem cell - some mutations results from identifiable (or unidentifiable) oncogenic influences - others are probably random errors that occur throughout life and accumulate in individual cells - many types of leukaemia increase steadily in incidence with the age of individuals due to a steady accumulation of mutations, some of which are harmful

Answer 334

- Down’s syndrome -\> associated with an increased propensity to ALL and AML - chromosomal fragility syndromes (inherited) - inherited defects in DNA repair - inherited defects of tumour-suppressor genes

Answer 335

- irradiation - anti-cancer drugs are themselves leukaemogenic - cigarette smoking - chemicals -\> e.g. benzene

Answer 336

o acute myeloid leukaemia = a failure of production of the end cells o chronic myeloid leukaemia = increased production of end cells - in AML, the responsible mutations usually affect TFs, so the transcription of multiple genes is affected -\> the production of an oncogene prevents normal function of the protein encoded by its normal homologue -\> cell behaviour is therefore profoundly disturbed - in CML, the responsible mutations usually affect a signalling protein gene -\> this gene encodes a protein in the signalling pathway between a cell surface receptor and the nucleus -\> protein encoded may be either a membrane receptor or a cytoplasmic protein - in CML, cell kinetics and function are not as seriously affected as in AML however, the cell becomes independent of external signals and alterations in the interaction with stroma occur -\> reduced apoptosis so that cells survive longer and the leukaemic clone expands progressively

Answer 337

o acute lymphoid leukaemias = an increase in very immature cells (lymphoblasts) -\> is a failure of these lymphoblasts to develop into mature T and B cells o chronic lymphoid leukaemias = leukaemic cells are mature, although abnormal -\> mature T cells or B cells are present but they may not be very functional

Answer 338

- leucocytosis -\> can lead to vessel obstruction - bone pain (if leukaemia is acute) -\> common in children with ALL - hepatomegaly and splenomegaly - lymphadenopathy (if lymphoid) and thymic enlargement (if T lymphoid) - skin infiltration - anaemia, neutropenia and thrombocytopenia -\> due to crowding out of normal cells - metabolic effects -\> weight loss, renal failure, sweating etc - immunological deficits -\> particularly in CLL -\> prodfound when advanced

Answer 339

- hyperuricaemia -\> uric acid in the blood is high due to increased breakdown of DNA - renal failure -\> as a result of uric acid depositing in the kidneys - weight loss - low grade fever - sweating

Answer 340

- bone pain is COMMON (particularly in the legs) - hepatomegaly and splenomegaly - lymphadenopathy and thymic enlargement (if T lineage) - testicular enlargement (due to infiltration of testes) o features due to the crowding out of normal cells - fatigue, lethargy, pallor, breathlessness (caused by anaemia) - fever and other features of infection (caused by neutropenia) - bruising, petechiae, bleeding (caused by thrombocytopenia)

Answer 341

- leucocytosis with lymphoblasts in the blood -\> sometimes are just in the bone marrow - anaemia (normocytic, normochromic) - neutropenia - thrombocytopenia - replacement of normal bone marrow cells by lymphoblasts

Answer 342

- before starting tests -\> clinical and familial history, and a physical examination - blood count and film - check of liver and renal function (may be impaired by infiltration) and uric acid measurement - bone marrow aspirate -\> for cytogenetic analysis - immunophenotyping - cytogenetic/molecular analysis - chest X-ray -\> look for thymus enlargement, and evidence of pneumonia

Answer 343

- a way of recognising the antigens expressed on the surface of cells -\> differentiates between cells of T-lineage or B-lineage - furthermore within each lineage, we can recognise different stages of maturation of blast cells -\> of prognostic importance o this is important because if can change treatment plans

Answer 344

- is the common antigen -\> expressed on B cells

Answer 345

- immature blast cells

Answer 346

- formation of a fusion gene -\> may result from translocation of chromosomes - dysregulation of a proto-oncogene by juxtaposition of it to the promoter of another gene -\> e.g. a T-cell receptor gene - point mutation in a proto-oncogene

Answer 347

- 12 and 21 -\> fusion to create the ETV6-RUNX1 gene on chromosome 12 - 10 and 14 -\> TLC3 gene becomes dysregulated by the proximity to teh TCRA gene - 4 and 11

Answer 348

- systemic (oral or IV) and intrathecal chemotherapy -\> leaukamia cells cross over the BBB and into the CSF -\> systemic chemotherapy cures systemic disease, but there can be relapse from CSF disease - supportive therapy -\> red cell transfusions (for anaemia), platelets (for thrombocytopenia) and antibiotics

Answer 349

- from top to bottom o epidermis o dermis -\> fat and subcutaneous tissue as well as blood vessels and nerves o hypodermis - muscle

Answer 350

- epidermis cells

Answer 351

- keratinocytes make up the BULK of the cells in the epidermis, but we also have melanocytes, Merkel cells and Langerhans cells (APCs involved in immunity) - keratinocytes start off at the bottom, and differentiate as they move towards the surface of the skin - keratinocytes sit on the basement membrane in the layer called the stratum basalae (basal layer of the epidermis) -\> where the keratinocytes start of, proliferate, and move on up the skin - as keratinocytes move towards the surface they change their morphology, becoming keratinocytes within the stratum spinosum (there are spines connecting cells together: desmosomes) - next layer up is the stratum granulosum: you can see granules in light microscopy - next layer is the stratum corneum -\> where cells are dead and have lost their nuclei

Answer 352

- keratinocyte derived -\> e.g. basal cell carcinoma, squamous cell carcinoma -\> are aka non-melanoma skin cancers - melanocyte derived -\> e.g. malignant melanoma - vasculature derived -\> e.g. Kaposi’s sarcoma, angiosarcoma - lymphocyte derived -\> e.g. Mycosis fungoides

Answer 353

- Kaposi's sarcoma

Answer 354

- genetic syndromes -\> Gorlin’s syndrome, Xeroderma pigmentosum - viral infections -\> HHV8 in Kaposi’s sarcoma, HPV in SCC - UV light -\> particularly for keratinocyte derived tumours (BCC, SCC) and malignant melanoma - immunosuppression -\> drugs, HIV, old age, leukaemia

Answer 355

- a new pigmented leison on the chest that STANDS OUT - is pigmented, has an irregular edge and has a nodule eccentrically placed as well as being asymmetrical in appearance

Answer 356

- studied with a dermatoscope (magnifying glass with a torch through it) - lesion is removed and pathologists observe it -\> see atypical melanocytes in an atypical architecture -\> thickness/depth of the mole determines the prognosis and treatment method - lymph nodes are palpated, have a skin check and are followed up every 3 months to detect whether there are signs of recurrence or metastases to the lymph node -\> if you have had one melanoma, you are more likely to have another one

Answer 357

- pale skinned/caucasians who spend lots of time in high UV exposed atmospheres

Answer 358

- basal cell carcinoma -\> usually occur on the face (this is just above the eyebrow - incidence has increased due to less people wearing hats

Answer 359

- UVC is completely filtered out in the ozone layer - UVB is partly filtered out - UVA can penetrate all the way below sea level -\> due to deeper penetration is the UV that causes skin ageing o UBV is considered to be the most significant, but the dose of UVA that penetrates to the surface of the Earth is much higher -\> BOTH are significant in causing skin cancer

Answer 360

o UVB induces mutations in the pyrimidines -\> cytosine and thymine bases - cyclobutane pyrimidine dimers form e.g. T=T, T=C, C=C - 6-4 pyrimidine-pyrimidine photoproducts - usually repaired quickly by nucleotide excision repair if not and in genes involved in the cell cycle it will lead to cancer

Answer 361

o UVA light also promotes skin carcinogenesis, but to a LESSER degree than UVB - can cause pyrimidine dimers and free radical production

Answer 362

o a recessive genetic condition with defective nucleotide excision repair -\> nucleotide excision repair is involved in a group of proteins that span the DNA, look for mutations and repair any abnormalities - these patients develop MULTIPLE skin cancers - condition can be managed provided that individuals are not exposed to UV light

Answer 363

- when someone gets sun burnt, they rapidly accumulate many mutations within their keratinocytes -\> because of this, many of the cells undergo apoptosis -\> prevents the cell from becoming cancerous

Answer 364

- UVA and UVB effects the expression of genes involved in skin immunity -\> depletes Langerhans cells in the epidermis, which are involved in immune responses -\> removal of damaged cells and apoptosis won’t work very well -\> cancers become more likely to occur - UV light causes reduced skin immunocompetence and immunosurveillance -\> basis for UV phototherapy (for e.g. psoriasis treatment) by suppressesing the inflammatory response within the skin

Answer 365

I = always burns, never tans -\> usually giner II = usually burns, sometimes tans -\> usually blonde III = sometimes burns, usually tans -\> usually have dark brown or black hair IV = never burns, always tans V = moderate constitutive pigmentation - south Asian VI = marked constitutive pigmentation - Afrocaribbean

Answer 366

- eumelanin -\> darker skinned people produce compartively more - phaeomelanin -\> lighter skinned people produce compartively more

Answer 367

o the amount and type of melanin produced -\> NOT the denisty of melanocytes - MCR1 gene determines the production of melanin - are over 20 gene polymorphisms within this gene -\> is variation in eumelanin:phaeomelanin produced, determined by the MCR1 gene -\> explains different hair colour and skin types

Answer 368

- melanocytes - Langerhans -\> are APCs

Answer 369

- is 1 melanocyte to every 5 keratinocytes o melanin is a chemical that helps protect the nuclei of keratinocytes against UV damage -\> skin is exposed to UV light and is susceptible to UV damage (sunburn) o if someone is exposed to UV light, keratinocytes produce melanocyte-stimulating hormone -\> has paracrine (local) effects on the melanocyte -\> stimulates melanin production o melanin is packaged into melanosomes, which travel down the dendritic processes -\> melanosomes are taken up by the keratinocytes and are positioned in front of their nuclei -\> protects the nuclei from UV-induced DNA damage

Answer 370

- melanocytes

Answer 371

- UV exposure - genetics play a fair role

Answer 372

- superficial spreading - nodular - lentigo maligna melanoma - acral lentiginous - amelanotic

Answer 373

- lentigo maligna occurs if the atypical melanocytes are restricted to the epidermis -\> there is proliferation of malignant melanocytes within the epidermis (in situ) -\> is therefore no risk of metastasis - often occur in elderly patients - are light and dark brown in colour, have irregular shape, are small (\>2cm) and are FLAT -\> usually occur on the face o NOTE -\> if there is invasion within a Lentigo maligna, it’s called a Lentigo maligna melanoma

Answer 374

- occurs where atypical melanocytes are in the epidermis, but have invaded the dermis - is both lateral proliferation of malignant melanocytes, and downwards proliferation -\> cells invade through the basement membrane, so there is a risk of metastasis - sometimes you get regression -\> where the melanocytes disappear as a result of immune response

Answer 375

o ABCD(E) - Asymmetry - Border irregular - Colour variation (dark brown-black) - Diameter \> 0.7mm and increasing - Erythema (redness) or Evolution (growing)

Answer 376

- it is regressing -\> immune response against it is effective - can mean there was a thicker melanoma in that area = worse prognosis

Answer 377

- vertical proliferation of malignant melanocytes (with no previous horizontal/lateral growth) -\> means that there is a risk of metastasis - can ulcerate

Answer 378

- downward proliferation of malignant melanocytes, following previous horizontal growth - nodule is developing within an irregular plaque -\> prognosis will become WORSE - tumour may be erythematous or if the tumour can’t make melanin, there will be non-pigmented components

Answer 379

- occur on the palms of the hand and soles of the foot - occur more frequently in darker-skinned people than other melanomas - is a darkly pigmented lesion, which starts of flat. It can develop lumps within it

Answer 380

- a melanomas that can't make melanin because they lose the ability to do so -\> results in a lesion that lacks pigment

Answer 381

- Breslow thickness -\> thickness measured from the top to the bottom of the lesion - \< 1 mm = superficial tumour - \> 1mm = deeper tumour

Answer 382

- personal history of melanoma - family history of dysplastic nevi or melanoma - skin type I or II - lots of UV irradiation and exposure -\> intermittent exposure on non-acclimatised (worse than constant as skin acclimatises) - sunburns during childhood - having atypical/dysplastic nevus syndrome (having lots of abnormal appearing moles)

Answer 383

- can be either quite rapidly growing, or slow growing - may occur in scars or scarring processes - is a risk of metastasis but it is relatively low risk

Answer 384

- keratinocytes -\> can therefore sometimes produce keratin

Answer 385

- benign lesion that looks very similar to a SCC

Answer 386

- lips -\> high sun exposure, smoking and drinking - ears are commonly targets in men -\> in general they don’t have hair to protect their ears from sun exposure - legs are common sites for SCC in women (due to increased exposure of the legs) - lips, ears and genital region are bad in terms of metastasis due large blood flow

Answer 387

- slow growing (a few millimetres a year) - invades tissue, but does not metastasise -\> can go into fat, muscle and bone, but don’t metastasise Common on the face and even th eyelid - often described as pearly (their surface glistens, and is often greyish) and flat

Answer 388

- keratinocytes at the basal layer of the epidermis

Answer 389

- UV exposure - HPV - immunosuppression

Answer 390

- UV exposure - genetics - immunosupression

Answer 391

- lymphoma os the skin - presents with patches of erythematous, scaly skin - is a patch stage,, plaque stage and tumour stage -\> is very slowly progressing -\> patients often outlive the disease - treated with chemo and radiation

Answer 392

- tumour is derived from the lymph endothelium - is related to HIV and aids -\> also DRIVEN by HHV8 - clinically, it looks like purple nodules on the skin

Answer 393

- a rare autosomal recessive condition which leads to the predisposition of HPV induced warts and SCCs - patient will be covered in little warts, which may be flat (right), or thick and keratotic (left)