Cancer Flashcards

Question

What is a cancer's stage?

Answer 1

A cancer’s stage is how well/far it’s spread.

Answer 2

Stage (metastasis)

Answer 3

- T describes the size of the original tumour and whether it has invaded nearby tissue (TX, Tin situ, T0, T1-T4) - N describes regional lymph nodes that are involved (Nx, N0-N3) - M describes distant metastasis (M0, M1)

Answer 4

- Maturity: embryonic cells divide at a much faster rate than adult cells - Complexity of the system: more complex cells have a slower rate of division - Necessity for renewal: skin and gastrointestinal epithelial cells divide every 20 hours, while hepatocytes divide every year. - State of differentiation: some cells such as neurones don’t ever divide. - Neoplasic cells have lost the ability to inhibit division

Answer 5

That there had been errors in cell division.

Answer 6

The cell cycle is an orderly sequence of events in which a cell duplicates its contents and divides in two.

Answer 7

- M-phase covers mitosis and cytokinesis | - Interphase covers G0, G1, S and G2

Answer 8

1. Cells are most easily killed in that state; Premature or aberrant mitosis leads to cell death. 2. DNA damage acquired during this phase cannot be repaired, and is passed on to daughter cells. 3. Gene transcription is silenced as chromosomes are being separated. 4. Metabolism is shut down to focus on mitosis.

Answer 9

- G0 is when the cell cycle machinery is dismantled, and the cell is functional. Most cells are at this state. - G1 is when the decision to divide has been made. - S is when DNA and organelles are duplicated as well as increase in protein synthesis. - G2 is when the cell checks everything is okay before proceeding towards mitosis.

Answer 10

It consists of two centrioles, a mother and daughter, which are barrels of 9 triplet microtubules.

Answer 11

The centrosome functions as a microtubule organising centre and mitotic spindle.

Answer 12

The daughter centrioles separate, duplicate, and thus form two centrioles in Late G1

Answer 13

Microtubules grow and polymerise from nucleating sites on centrosomes.

Answer 14

Prophase mainly involves the condensation of chromatin to form chromosomes. In late prophase, the homologous pair of chromosomes migrate to opposite sides of the nucleus and the mitotic spindle forms outside the nucleus: - Radial microtubules arrays (Asters) form around each centrosome. - The radial arrays meet, determining the polar microtubules

Answer 15

As the DNA is already duplicated, there are two sets of DNA in the nucleus. The DNA wraps around histone proteins to form chromatin, which then pack closer to form nucleosomes. These eventually coil together to form a chromatid. The sister chromatids join at the centromere to form a chromosome.

Answer 16

In early prometaphase there is breakdown of the nucleus, followed by the attachment of the chromosomes to the spindle via the kinetochores on each sister chromatid. In late prometaphase the microtubules from opposite poles are captured by sister kinetochores. Chromosomes attached to each pole congress in the middle. It is metaphase when the chromosomes are at the equator.

Answer 17

Anaphase A: there is a signal to break down cohesin (the protein that holds the chromatids together), allowing the separation of the chromatids. At anaphase B, the daughter chromosomes migrate towards the poles, while the centrosomes migrate apart.

Answer 18

Telophase begins when the sister chromatids have reached opposite poles, arriving at the centrosome spindles. The nuclear envelope reassembles around the chromosomes at opposite ends. A contractile filament ring assembles around the equator, forming the cleavage furrow, which will contract to split the cell in two.

Answer 19

Mitosis ends when new membrane is inserted between the cells, essentially separating them. The acto-myosin ring contracts to divide the cell. A midbody is left between the cells, which is composed of residual spindle fibres. After cytokinesis, interphase microtubule array reassembles, chromatin decondenses and nuclear substructures reform.

Answer 20

There is a mitotic checkpoint between prometaphase and metaphase controlling weather a cell progresses into anaphase.

Answer 21

CENP-E sense when kinetochores are attached. BUB protein kinases then dissociate from the kinetochore when the chromosomes are properly attached to the spindle. Only when all the BUBs are dissociated, can anaphase proceed.

Answer 22

- Syntelic is when both sister chromatids are attached to the same centrosome pole. - Merotelic is when one kinetochore is connected to two microtubules from both centrioles, resulting in a broken/lost centrosome in cell division. - Monoletic is when only one chromatid is attached.

Answer 23

- A checkpoint kinase inhibitor will allow the tumour cells to produce gross chromosome mis-segregations, which will eventually cause the cell to undergo apoptosis. - Taxanes and Vinca Alkaloids alter the microtubule dynamics leading to unattached kinetochores. This therefore causes long-term mitotic arrest.

Answer 24

- There is a checkpoint at late G1 before entering S phase. The cell will only continue to S phase if the cell is big enough - There is another checkpoint at G2, before the onset of mitosis. The cell can only continue if the cell size and external environment are correct, as well as accurate and complete DNA replication takes place.

Answer 25

1. Cell cycle arrest – at the checkpoints. This can be temporary, until the parameter has been fixed. 2. Apoptosis – happens if DNA damage is too great, or if there are chromosomal abnormalities or toxic agents present.

Answer 26

Mitogenic signal

Answer 27

Growth factor peptides are dimers which bind simultaneously to two tyrosine kinase receptors, bringing them together. This allows the cytoplasmic tails of the receptor (containing the tyrosine kinases) to cross-phosphorylate each other. This creates multiple phosphorylated tyrosine residues, which act as docking sites that recruit other proteins.

Answer 28

Once the tyrosine kinase receptor is activated, an adaptor protein called GRB2 hooks onto a phosphate group and recruits an exchange factor called SOS. SOS activates a membrane-bound signaling (GTP binding) protein called Ras, which is normally inactive bound to GDP. SOS catalyses the exchange of GTP from the cytoplasm to the Ras protein, changing the conformation and activating it.

Answer 29

GTPase Activating Proteins (GAPs) turn off the Ras

Answer 30

- Membrane bound - GTP binding protein - Normally bound to GDP and inactive - Activated by exchange factors (SOS) which change GDP with GTP - Activates protein kinase cascade

Answer 31

1. Glycine at position 12 valine: prevents GAP binding and therefore preventing Ras inactivation 2. Glutamine at position 61 leucine prevents GTP hydrolysis as glutamine is normally involved in the intrinsic GTPase activity of Ras

Answer 32

GTP-Ras activates a protein kinase cascade by binding to the first kinase in the ERK (Extracellular Signal-regulated Kinase) cascade. The final MAPK phosphorylates Myc

Answer 33

Mitogen Activated Protein Kinase

Answer 34

- The first kinase (generically called MAPKKK), called Raf, phosphorylates to activate the second kinase, using ATP. - The second kinase (generically called MAPKK), called MEK, phosphorylates to activate the second kinase, also using ATP. - The last kinase (generally called MAPK), called ERK, phosphorylates target proteins involved in gene transcription and protein synthesis. An example of a transcription factor activated is Myc.

Answer 35

Cyclin-dependent kinases (Cdks) also called cyclically activated protein kinases .

Answer 36

serine/threonine kinases

Answer 37

Cyclins and phosphorylation (twice, then one is removed)

Answer 38

Cdks are always expressed Different cyclins are expressed transiently through the cell cycle. First cyclin D at the end of G1, then cyclin E, then cyclin A and finally cyclin B.

Answer 39

The Cdk-cyclin complexes are further regulated by two kinases. CAK (Cdk Activating Kinase) phosphorylates one site on Cdk1 to promote Cdk1 activity – positive phosphorylation. Wee1 phosphorylates another site on to inhibit Cdk1 activity – negative phosphorylation. A Cdk with two phosphate groups is still inactive. In order for it to be catalytically active, the inhibitory phosphorylation must be removed by Cdc25, a phosphatase.

Answer 40

Active MPF (Cdk1-CyclinB) has a positive feedback effect on Cdc25 by stimulating phosphorylation of the inactive Cdc25 which can dephosphorylate more inactive MPF more active MPF

Answer 41

MPF (maturation promoting factor)

Answer 42

In the early phase of mitosis, active MPF phosphorylates many substrates required for mitosis. The Cdk1-cyclinB complex holds mitosis until a signal is received that all kinetochores are attached to the spindle. When all kinetochores are attached, cyclinB degradation is triggered. This leads to the inactivation of Cdk1 and key substrates are dephosphorylated so that mitosis can proceed at the metaphase-anaphase transition.

Answer 43

The Cdk1-cyclinB (MPF) complex is only activated at the start of mitosis and is deactivated before anaphase

Answer 44

One of the main genes ‘activated’ by c-Myc (transcription factor stimulated by growth factor) is that which codes for cyclinD. CyclinD is able to form complexes with Cdk4 and Cdk6. (then cyclin E, then A then B)

Answer 45

- Cdk4/6-cyclinD from G0 to G1 - Cdk2-cyclinE from G1 to S - Cdk2-cyclinA from S to Mitosis - Gdk1-cyclinB from Prophase to Anaphase

Answer 46

CyclinE is then able to form a complex with Cdk2, which is needed to move the cell from G1 to S phase. An example of a protein phosphorylated by cyclinE is the RetinoBlastoma (RB) protein - pRB, which is inactivated by phosphorylation. When inactivated, the conformational change allows the release of a transcription factor E2F. Among other proteins, E2F allows for the transcription of further cyclinE

Answer 47

The RB protein is normally active, holding transcription factor E2F in place. When phosphorylated (twice) it is inactivated, letting lose E2F which up regulates transcription of cyclinE

Answer 48

- Wee1 | - CKIs (Cdk Inhibitors)

Answer 49

- The INK4 family is active in G1, to inhibit Cdk4/6-cyclinD complexes by displacing cyclinD. There is a balance between cyclin D binding to Cdk4/6 and INK4 binding to control progression through G1. - The CIP/KIP family is active in S phase to inhibit all Cdk complexes by binding to the entire complex itself

Answer 50

The oncogenes (mutated proto-oncogenes) include: - EGFR/HER2 (receptors) mutationally activated or overexpressed in many breast cancers - Ras mutational activation in many cancers - CyclinD is overexpressed in 50% of breast cancers - B-Raf (top kinase in ERK cascade) mutationally overactivated in melanomas - c-Myc overexpression in many tumours Tumour suppressors include: - RB is inactivated in many cancers - CKI under-expression in many cancers

Answer 51

Surgery Chemotherapy Radiotherapy Immunotherapy

Answer 52

- Cytotoxic chemotherapy | - Targeted therapies

Answer 53

- Alkylating agents - Anti-metabolites - Anthracyclines - Vinca Alkaloids and Taxanes - Topoisomerase inhibitors

Answer 54

- Small molecule inhibitors | - Monoclonal antibodies

Answer 55

Cytotoxics ‘select’ rapidly dividing cells by targeting their structures. They target DNA, apart from Vinca Alkaloids and Taxanes which target mitotic spindles. [Cytotoxic drugs are usually given intravenously, but occasionally orally.] Because of its systematic nature, they target all rapidly dividing cells.

Answer 56

Side effects include: hair loss, nausea, vomiting, damaged nails, fatigue, weight loss, anorexia and immunosuppression (as bone marrow cells are also rapidly dividing, there is lowering of the neutrophil count causing neutropenia), nephrotoxicity, neurotoxicity and diarrhoea.

Answer 57

When a treatment is given pre-operatively, it can be described as an neoadjuvant. When given post-operatively, it can be described as an adjuvant.

Answer 58

Alkylating agents add alkyl groups (CnH2n+1) to guanine residues in DNA. This allows the formation of cross-links between the stands, entire DNA molecules and between the DNA and histones. This will ultimately lead to apoptosis via a checkpoint mechanism as the DNA cannot unwind.

Answer 59

The addition of alkyl groups to guanine residues leads t the risk of secondary malignancies as they encourage miss-pairings.

Answer 60

Alkylating agents add alkyl groups to guanine residues. Pseudoalkylating agents add a platinum group to guanine residues instead.

Answer 61

- hair loss - nephrotoxicity (alkylating) - neurotoxicity - ototoxicty (platinum) - nausea - vomiting - diarrhoea - immunosuppression - tiredness.

Answer 62

Anti-metabolites masquerade as purine or pyrimidine residues. They replace bases during DNA synthesis, leading to breakages in the DNA double strand and therefore apoptosis. Also blocks transcription. They can also be folate antagonists which prevents the formation of folate acid, an important building block for many amino acids.

Answer 63

alopecia, immunosuppression, nausea and vomiting, diarrhoea, palmar-plantar erythrodysesthia and fatigue

Answer 64

Anthracyclins fit in between (intercalate) DNA strands, inhibiting transcription and replication. They also generate free radicals that can damage DNA and cell membranes. Because they block DNA repair, they are mutagenic.

Answer 65

Side effects of antracyclins include hair loss, fatigue, vomiting and nausea, immunosuppression, skin changes, cardiac toxicity, and red urine.

Answer 66

Vinca Alkaloids inhibit microtubule assembly and Taxanes inhibit microtubule disassembly.

Answer 67

Side effects include: nerve damage (peripheral neuropathy, autonomic neuropathy, alopecia, nausea and vomiting, immunosuppression, arthralgia and allergy.

Answer 68

Topoisomerases prevent DNA torsional strain during DNA replication and transcription by introducing single (topo1) or double (topo2) strand breaks in the poshphodiester backbone of DNA. Inhibiting this leads to permanent DNA breaks --> apoptosis of the cell.

Answer 69

Anthracyclines

Answer 70

Side effects include alopecia, nausea and vomiting, fatigue, immunosuppression and acute cholinergic type syndrome (irinotectan) which is diarrhoea, abdominal cramps, and diaphoresis (sweating) – therefore given with atropine.

Answer 71

Cancer cells can become resistant to some of the cytotoxic drugs. They do this by acquiring mutations, which are then naturally selected for during treatment. Therefore, drugs are often given in combination as it is unlikely the cell can squire both resistant mutations.

Answer 72

- DNA repair mechanisms upregulated --> no double-stranded breaks and thus no apoptosis. - DNA adducts are replaced by Base Extinction repair - Drug efflux from the cell using ATP-binding cassette transporters

Answer 73

1. Self-sufficient: normal cells need growth signals to move into the cell cycle 2. Insensitive to anti-growth signals 3. Anti-apoptic 4. Pro-invasive and metastatic 5. Pro-angiogenic 6. Non senescent 7. Dysregulated metabolism 8. Immune system evasion 9. Unstable DNA 10. Inflammation

Answer 74

Monoclonal antibodies (mAbs) can bind to the growth factors to prevent them causing receptor dimerisation and thus leading to mitotic signalling pathway. mAbs can also bind to the ligand binding sites on the receptor itself, preventing ligand binding. This type of binding also causes receptor internalisation and thus down-regulating the number of expressed receptors.

Answer 75

Bevacizumab binds to and neutralises the VEGF receptor, improving survival in colorectal cancer. Cetuximab targets the extracellular portion of EGFR to prevent it dimerising.

Answer 76

Intravaenously

Answer 77

- momab refers to antibodies from mice - ximab refers to chimeric antibodies - zumab refers to humanised antibodies - mumab refers to fully human antibodies

Answer 78

Small molecule inhibitors bind to the intracellular portion of the tyrosine kinase receptors, preventing autophosphorylation and thus blocking downstream signalling. They can also block the receptor domain. [It can be given orally]

Answer 79

The (9,22) chromosome translocation in patients with chronic myeloid leukaemia is targeted as it was found to create a fusion protein (called Bcr-abl) containing a tyrosine kinase, which was found to cause over-production of white blood cells. Glivec is a small molecule inhibitor that only targets the Bcr-abl ATP binding region within the tyrosine kinase domain.

Answer 80

the case was an example of an ‘Oncogene addicted’ cancer. This is when a single mutation is the diving force of the tumour and can therefore be seen as it’s ‘Achilles’ Heel’

Answer 81

The main advantages of using targeted therapies in the blockage of cancer hallmarks the without toxicity seen in cytotoxic drugs. Targeted therapies can also inhibit angiogenesis and anti-apoptosis.

Answer 82

a major disadvantage of targeted therapies is the ability for the tumour to develop resistance easily

Answer 83

- Mutation in the ATP binding region of the Bcr-abl protein allowing only ATP to bind and not Glivec. - Intrinsic resitance (Herceptin is only effective in 85% of HER2+ breast cancers, suggesting other driving pathways) - Intragenic mutations - Upregulation of downstream or parallel pathways

Answer 84

Anti-sense oligonucleotides can hinder translation of specific mRNA. They can also recruit an enzyme to cleave the target mRNA. This is particularly useful for ‘undruggable’ targets. RNA interference is a single stranded complementary RNA which recognises and destroys mRNA, preventing the ‘bad’ protein(s) from being synthesised. However, this technique has lagged behind anti-sense technology – especially in cancer therapy. Furthermore, all these treatments are very expensive and the NHS cannot afford them.

Answer 85

Chemical – hormones, growth factors, ion concentrations, ECM, molecules on other cells, nutrients and dissolved gas concentrations Physical – mechanical stresses, temperature and the topography of the ECM.

Answer 86

- Growth factors - Cell-cell adhesion - Cell-ECM adhesion

Answer 87

In suspension cells do not significantly synthesise proteins or DNA; cells require ECM attachment and a certain degree of spreading (important) to begin protein synthesis and DNA replication

Answer 88

It requires energy to modulate cell adhesion and the cytoskeleton during spreading

Answer 89

They require ECM attachment and cell spreading

Answer 90

Integrins as they have lots of functions such as a role in development, the immune system, clotting system etc.

Answer 91

Most integrins are linked to the actin cytoskeleton through actin-binding proteins. An exception to this is the α6β4 integrin which is found in epithelial hemidesmosomes (basal structures associated with epithelial cells) and is linked to the cytokeratin (Intermediary Filaments of epithelial cells) network.

Answer 92

Integrins are heterodimeric complexes of α and β subunits that are associated by their head regions. Each of their tail regions spans the plasma membrane into the cytoplasm.

Answer 93

The head regions must bind to divalent cations such as calcium for their function.

Answer 94

There are 10 α units and 8 possible β subunits to make 20 combinations of integrin molecules.

Answer 95

Focal adhesions

Answer 96

Focal adhesions are a way for the cell to interpret the environment around it. Ligand binding extends the tails of the integrein complex allowing cytoplasmic signalling and actin assembly.This is called outside-in signalling and can alter the phenotype of the cell. Inside-out signalling is when a hormone can alter the affinity of the integrin.

Answer 97

Density dependence (competition for external growth factors), previously thought to be related to 'contact inhibition'

Answer 98

There is cross-talk between growth factor signalling and ECM signalling. There is a convergence in the signalling of their pathways to produce proliferation. Individually, their activation of signalling pathways are weak, but together it is strong and sustained.

Answer 99

- Short-term contact is when the transient interactions between the cells do not form stable cell-cell junctions. - Long-term contact is when there are stable interactions leading to the formation of cell-cell junctions.

Answer 100

They actually ‘repel’ one-another by paralysing motility at the site of contact. This in turn promotes the formation of a motile front at the opposite site allowing the cell to move away.

Answer 101

contact inhibition of locomotion

Answer 102

epithelial or endothelial cells

Answer 103

These can be arranged continuously (zonulae) or in discrete spots (maculae).

Answer 104

Contact between endothelial cells leads to stable adhesions and mutual induction of spreading. Cell-cell contact leads to lower proliferation of the cells.

Answer 105

Adherens junctions are one of the most important types of cell-cell junctions. They use ca2+ dependent cadherin adhesion molecules to form a complex junction. Extracellular, CADHERIN associates with with identical molecules on adjacent cells. Intracellularly, the cadherin cytoplasmic tails associate with a β-CATENIN molecule, which associates with an α-CATENIN molecule, which associates with an actin filament.

Answer 106

In the cytoplasm, β-catenin associates with LEF-1 forming a transcription factor, leading to proliferation. When bound to cadherin, β-catenin is not available for LEF-1 association and therefore inhibits proliferation. - also activates Rac and inhibits Rho - some growth factor receptors are associated with cell-cell junctions

Answer 107

APC gene-product is a protein that normally degrades beta-catenin in the cytoplasm. Without this, more beta-catenin can bind to LEF-1 to form a transcription factor leading to proliferation.

Answer 108

The Hayflick limit

Answer 109

Metastasis of a primary carcinoma cell only works when cell-cell adhesion is down-regulated. Cells must be motile in order to spread. Degradation of the ECM must also take place, and so matrix metalloproteinase levels are increase to migrate through the basal lamina.

Answer 110

proto-oncogenes

Answer 111

- organogenesis - wound healing - growth factors/chemoattractants - de-differentiation (in tumours)

Answer 112

By the polarity of the cell

Answer 113

The substratum

Answer 114

Hapoptatic motility is movement with no direction. Chemotactic motility is where the cell senses a stimuli and goes towards it.

Answer 115

Actin filaments

Answer 116

- Filopodia are finger-like projections rich in actin filaments, used by the cell to sense the environment. The actin forms tight parallel bundles which do not contract. - Lamellipodia are sheet like protrusions rich in actin filaments, which attach to the substratum via focal adhesions to move the cell forward. Here the actin is branched and cross-linked. - In stress fibres, they form anti-parallel, contractile bundles (which contract to slide past each other and shorten). - Microvilli - Stereocilia

Answer 117

- Sequestering proteins bind to the G-actin monomers and hold them in a pore until they are required. - Nucleating proteins are made to initiate the polymerisation of actin to generate the filament - Motor proteins provide contraction and other proteins bind to generate a filament. - Capping proteins are stop signals to prevent further growth - Severing proteins are like scissors

Answer 118

Nucleation is the limited step in actin dynamics, it is the formation of trimers to initiate polymerisation of filaments.

Answer 119

Arp2 and Arp3 (actin related proteins) are proteins that stabilise the point at which nucleation starts, forming an Arp23 complex which is able to bind a trimer of actin monomers.

Answer 120

Profilin exchanges ADP in G-actin to ATP which makes it easier to join the filament. Thymosin forms complexes with G-actin, preventing it from polymerising. The balance between these two proteins regulate the rate of filament growth

Answer 121

* At the positive end, these include: Cap Z, Gelosin and Fragmin/Severin. * At the negative end, these include: Tropomodulin and Arp Complex.

Answer 122

Severing is a scissor-like activity to cut the filaments in order to depolymerize and dissemble the filaments for quick remodelling of the cytoskeleton and a burst of new polymerisation.

Answer 123

Severing proteins include: Gelsolin, ADF/Cofilin and Fragmin/Severin.

Answer 124

Cells move forwards by lamellae protrusions, where there is net filament assembly at the leading edge, and disassembly behind it. The filaments at the assembled edge are eventually branched and capped. It is the addition of monomers which provides the force behind the movement. At the back of the lamaellae protrusions the filaments are disassembled by severing proteins to detach branches which are not needed.

Answer 125

Filopodia form with actin polymerisation, building and cross-linking to form tightly-packed parallel bundles. The polymerisation begins at the amorphous region (end of the finger), building actin filaments towards the cell rather than away.

Answer 126

* Ion flux changes, such as calcium ion influx * Phosphoinositide signalling – phospholipid binding * Kinases/phosphatases activate/inactive cytoskeletal proteins * Signalling cascade via small GTPases

Answer 127

The actin cytoskeleton can also be controlled by small G-proteins of the Ras superfamily (of which also include Rac, Rho and Cdc42). The proteins can be activated by tyrosine kinase receptors, adhesion receptors and signal transduction pathways. These active G-proteins bind to effector proteins such as WASP, Profilin etc., to carry out specific functions: • Filopodia are activated by Cdc42 • Lamellipodia are activated by Rac • Stress fibres (bundles of contractile filaments) are activated by Rho. (Too much Rho can cause the cell to shrink and detach due to uncontrollable contraction).

Answer 128

1. Death of harmful cells (with damaged DNA that could potentially turn malignant) 2. Developmentally defective cells need to die (such as in central tolerance) 3. Excess/unnecessary cells also need to be removed. Such cells can include those between the digits during development 4. Removal of obsolete cells such as mammary epithelium after lactation 5. Exploration of the mechanisms by chemotherapy.

Answer 129

Necrosis is unregulated cell death associated with trauma, cellular disruption and an inflammatory response

Answer 130

Traumatic damage causes the cell membrane to become more permeable. This leads to the cell swelling and eventually rupture of the membrane, leading to the release of proteases. This causes autodigestion, creating a mess of cellular material which attracts phagocytes and causes localised inflammation.

Answer 131

Apoptosis is regulated cell death with controlled disassembly of cellular contents without disruption nor an inflammatory response.

Answer 132

* Loss of microvilli and intercellular junctions * Cell shrinkage * Loss of plasma membrane asymmetry (phosphatidylserine is normally only on the interior side of the membrane, but now on the outer – can be used to detect apoptotic cells) * DNA fragmentation * Formation of membrane blebs * Fragmentation into membrane-enclosed apoptotic bodies

Answer 133

Due to loss of plasma membrane asymmetry - phosphatidylserine (normally only on the interior side of the membrane) is now on the outer side of the membrane.

Answer 134

DNA cut in a regular manner by specific CADs (Caspase Activated Dnase)

Answer 135

- Death receptor trimerisation (death by design) | - Intrinsic breakdown of the mitochondria (death by default)

Answer 136

Caspases (Cysteine-dependent Aspartate-directed Proteases)

Answer 137

They have a cysteine residue in the active site which is required for the catalytic properties of enzyme. They cut the protein after the aspartate residue. Caspases are themselves also activated by proteolysis, which triggers a cascade of activation.

Answer 138

Initiator caspases and effector caspases.

Answer 139

2, 8, 9 and 10 | Plan 10

Answer 140

Initiator caspases have protein-protein interaction domains before their p20 and p10 subunits. These can either be CARD or DED domains.

Answer 141

p20 and p10 subunits.

Answer 142

Activator caspases need to be cleaved twice. After cleavage, the molecules fold into an active hetero-tetrameric capsule molecule, where two small subunits and two large subunits combine. The active hetero-tetramer is the enzyme that will go to cleave target proteins.

Answer 143

homotypic binding

Answer 144

All cells have one or more members of the death receptors (such as the Fas ligand). They have cysteine-rich extracellular domains and a cytoplasmic Death Domain (DD). The monomeric receptors are only activated when bound to a specific trimeric ligand.

Answer 145

1. Fas-Ligand on cytotoxic CD8+ T-lymphocytes can bind to the Fas receptor on a cell, causing the trimerisation of the receptor. 2. The DDs of the Fas receptors interact with the DD of an adaptor protein called FADD 3. The DED region of FADD interacts with the DED domain of procaspase 8 4. This causes the oligomerisation of procaspase 8 leading to the formation of Death Inducing Signalling Complex (DISC). Oiligomerisation allows the cross-cleavage of three procaspase 8 molecules eventually leading to an active initiator caspase 8 tetramer being formed. 5. This goes in to activate a cascade of caspases (mainly through caspase 3)

Answer 146

Another adaptor protein called FLIP

Answer 147

This because it has two DED domains, and so competes with procaspases. It has no proteolytic activity and so does not activate cause a caspase cascade.

Answer 148

Cellular stress such as lack of stimulation from growth factors, or damage can interfere with mitochondrial transmembrane potential (used to make ATP via the electron transport chain). This causes the release of cytochrome-c and other other apoptosis-inducing factors into the cytoplasm.

Answer 149

The apoptosome is made of Apaf1 (apoptotic activating factor-1), procaspase 9, cytochrome-c and ATP. When cytochrome-c is released from the mitochondria, it binds to the WD-40 domain of the Apaf1 protein (outer end). This triggers a conformational change in the Apaf1 protein causing it to form a heptamer. This assembly is ATP-dependent. The CARD domains are centered in the middle, allowing association with the CARD domain on procaspase 9. This completes the formation of the apoptosome.

Answer 150

caspase 2 and 9 contain CARD domains | Caspase 8 and 10 contain TWO DED domains

Answer 151

The 7 procaspase 9 molecules in close proximity leads to cross-cleavage and release active caspase 9. Caspase 9 also initiates the caspase cascade.

Answer 152

Caspase 8 (from the extrinsic pathway) can also cleave a protein called Bid which enhances release of cytochrome-c from the mitochondria.

Answer 153

The mitochondrial pathway requires ATP, therefore the energy levels of the cell can determine where on the gradient of apoptosis to necrosis the cell falls at. Low ATP levels will result in necrosis as the mitochondrial apoptotic pathway cannot be engaged.

Answer 154

PI3’-Kinase Pathway

Answer 155

The docking site on the EGFR allows the binding of the adaptor protein p85, which associates with protein p110 – together forming the PI3’-Kinase. The lipid kinase phosphorylates the cell membrane lipid PIP2 to PIP3. PIP3 is now a docking site for the protein kinase PKB/Akt. This kinase phosphorylates and inactivates pro-apoptotic protein Bad.

Answer 156

Normally, anti-apoptotic proteins (Bcl-2 and Bcl-xL) hold the pro-apoptotic proteins (Bax) in place, inactivating them through their BH3 domains.

Answer 157

When there are not enough survival signals, the PKB/Akt protein no longer back Bad, which competes for the BH3 domains of Bcl-2. This releases Bax and Bak proteins, allowing them to create a pore in the mitochondrial membrane, facilitating the release of cytochrome-c formation of the apoptosome.

Answer 158

Proto-oncogenic

Answer 159

Bcl-2 and PKB/Akt

Answer 160

Proto-oncogenes code for essential proteins involved in the maintenance of cell growth, division and proliferation. A mutation coverts a proto-oncogene to an oncogene, whose protein product no longer responds to control influences.

Answer 161

Tumour suppressor genes typically code for proteins that regulate cellular proliferation and maintain cell integrity

Answer 162

- Each cell has two copies of TS genes. Mutation or loss of both genes means a loss of control, leading to cancer - Oncogenes can be aberrantly expressed, over-expressed or aberrantly active.

Answer 163

- Point mutation/deletion/insertion can code for an active aberrant protein. - Gene amplification – multiple copies of the same gene leads to protein overproduction - Chromosomal translocation – places genetic material next to, or on an oncogene. Genetic material placed before the proto-oncogene can enhance expression of the protein. Genetic material placed in the middle of a proto-oncogene creates a fusion protein, which may also be hyperactive - Insertional mutagenesis – where a viral infection inserts genetic material, and can lead to the formation of an oncogene by the aforementioned mechanisms.

Answer 164

fusion protein created by a chromosomal translocation is the case of the Philadelphia chromosome. It is the result of a reciprocal translocation between chromosome 9 and chromosome 22, which is specifically designated t(9;22)(q34;q11). This leads to the formation of leads to the formation of the BCR-ABL fusion protein.

Answer 165

- Tyrosine kinase receptor – met and neu genes. - G-protein coupled receptor – Ras and gip-2 genes. - Nuclear or cytosolic receptor – Myc, fos and jun genes. - Signal transduction – src, ret, raf and pim-1 genes.

Answer 166

1. Glycine at position 12 valine: prevents GAP binding and therefore preventing Ras inactivation 2. Glutamine at position 61 leucine prevents GTP hydrolysis as glutamine is normally involved in the intrinsic GTPase activity of Ras, and so prevents inactivation.

Answer 167

a) SRC, a Tyrosine Kinase that is over-expressed b) MYC - a Transcription Factor that is translocated b) Ha-RAS a G-protein point-mutated

Answer 168

a) JUN - an overexpressed transcription factor | b) Ki-RAS a point-mutated G-protein

Answer 169

* Regulate and control cell proliferation * Maintaining cellular integrity * Regulate cell growth * Regulate cell cycle * Nuclear transcription factors * DNA repair proteins * Cell adhesion molecules * Cell death regulators

Answer 170

a) p53 a cell cycle regulator b) BRCA1 a cell cycle regulator c) PTEN a tyrosine and lipid phosphatase

Answer 171

a) APC a cell signalling molecule b) p16Y-INK4A a cell cycle regulator c) MLH1 a mismatch repair gene

Answer 172

- Family history of related cancers e.g. breast and prostate cancer runs in families - Unusually early age of onset e.g. at birth, more susceptible to developing a tumour due to inheriting bad genes - Bilateral tumours in paired organs e.g. inherited susceptibility means more likely to get cancer in both kidneys - Synchronous or successive tumours e.g. p53 mutation leads to multiple cancers - Tumours in different organ systems in same individual e.g. p53 mutation leading multiple tumours in different organs - Mutation inherited through the germline

Answer 173

The RB1 gene is a tumour suppressor that needs both copies faulty to cause retinoblastoma. People can inherit a faulty copy.

Answer 174

RB1 tumour suppressor gene on chromosome 13q14.

Answer 175

Familial adenomatous polyposis coli is a distressing condition of the colon caused by faulty APC tumour suppressor gene. Individuals who have don’t have a working copy, get many polyps on their colon due to hyperproliferation. APC is involved in cell adhesion and signalling, controlling the activity of β-catenin. Polyps are tissue that are no longer responding to external stimuli and therefore acquire further genetic damage which can lead to colorectal cancer.

Answer 176

p53 is a transcription factor, described as the guardian of the genome as it regulates transcription of various genes, including those involved in DNA repair and antioxidant defence.

Answer 177

It is normally inactive, bound to a protein called MDM2. If anything disturbs the binding, p53 is released and therefore active. Disturbances can include oxidative stress, ribonucleotide depletion, oncogene activation and especially DNA damage. If stress on p53 is mild, then the activities of p53 transcription products can deal with the situation. If the stress is too severe, p53 will guide the cell to apoptosis.

Answer 178

Although p53 is a tumour suppressor, it’s mutated alleles act in a dominant manner mutation of a single copy is enough to cause dysregulation of its tumour suppressor activities.

Answer 179

. Damage to either proto-oncogene or both TS genes encourage proliferation and growth. Note this is not cancer yet, but has a cancer-like genotype. The lack of regulation also allows the cell to acquire more damage cancer (multi-step phenomenon).

Answer 180

Although cancer incidence is increasing worldwide, the rate of cancer mortality is decreasing (or stabilising).

Answer 181

The main types of cancers that affect people around the world are: prostate, breast, lung, liver, and colorectal cancer.

Answer 182

Incidences of liver, stomach and oesophageal cancers are high in developing countries due to their infectious causes (such as Hep B/C and H Pylori)

Answer 183

The most lethal cancer (smallest gap between incidence and mortality) is pancreatic, followed by lung and oesophageal cancer

Answer 184

Incidence of prostate cancer is greater in developed countries; can be attributed to early diagnosis by PSA test. Survival is much better in prostate cancer particularly in HICL because PSA screening is more available in HIC and leads to early detection and therefore decreased mortality rate.

Answer 185

Decreased incidence of stomach cancer in developed countries could be attributed to improved storage of food (refrigerators) reduction in Helicobacter Pylori reduction in stomach cancer.

Answer 186

Breast cancer

Answer 187

Approximately 16% of cancers are a result of infection worldwide – this average is greater in developing countries.

Answer 188

- Cervical, head and neck cancers --> Human Papilloma Virus - Hodgkin’s and Burkitt’s lymphoma --> Epstein-Barr Virus - Liver cancer --> Hepatitis-C Virus, Hepatitis-B Virus - Stomach cancer --> Helicobacter Pylori

Answer 189

- Migrant studies have shown that there is a rapid change of cancer risk following migration pointing towards lifestyle/environmental factors. - Time trends of cancers move too quickly to be influences by genes, and so are influenced by environmental factors instead. - Geographical distribution of cancers does not match the geographical distribution of genes.

Answer 190

The secular trend in cancer rates is the increase in incidence but decrease in mortality

Answer 191

can be attributed to a range of factors, not just an improvement in treatment: better completeness of data and different data classifications, better diagnostic techniques, better screening practices, demographic changes and changes in risk factors.

Answer 192

- Smoking accounts for at least 30% of all cancer deaths - Diet: as dietary fiber increases, risk of colorectal cancer decreases - Alcohol affects oral cavity, pharynx, larynx, oesophagus and liver; synergism with tobacco and balance with preventative effect for CHD - Hormones: e.g. risk of breast cancer increases with levels of different hormones increased; Oestradiol leads to increased risk of breast cancer. - Infection - Occupation

Answer 193

- Acute Lymphatic Leukaemia - treatable and curable with high success rates in developed countries. - Lymphomas - Nervous system tumours - neuroblastomas - Heterogeneous groups of tumours e.g. Renal tumours and sarcomas

Answer 194

A) Vasculogenesis - is the differentiation of precursor cells (from bone marrow) into endothelial cells and the de novo formation of a primitive vascular network. B) Angiogenesis - the physiological process through which new blood vessels form from pre-existing vessels. C) Arteriogenesis – the increase in the diameter of existing arterial vessels

Answer 195

Cells contain HIF (Hypoxia Inducible Factor) – a highly evolutionarily conserved transcription factor. In the presence of oxygen HIF is bound to pVHL (protein of the tumour suppressor gene Von Hippel-Lindau), which facilitates HIF destruction by the ubiquitin pathway. In the absence of oxygen, HIF is no longer bound, and can promote transcription of a large variety of genes. One important family of genes transcribed are the VEGF (Vascular Endothelial Growth Factor) genes.

Answer 196

There are five members of the VEGF family: VEGF-A,B,C,D and PIFG (placental growth factor).

Answer 197

Even though a number of endothelial cells would be exposed to VEGF, only one becomes a tip cell, while the other adjacent cells become stalk cells (supporting role).

Answer 198

Tip cells undergo dramatic conformational changes and project filopodia. - produces metalloproteinases to dissolve the basement membrane - expresses avb3 and avb5 integrins that act as grappling hooks, allowing the cells to sprout forwards

Answer 199

The tip cells of different vessels fuse with each other forming a new vessel. The vessel is stabilised by specialised muscle cells called pericytes. Cadherin molecules are also important in creating tight cell- cell junctions.

Answer 200

thrombospondin-1

Answer 201

Tip selection is based on notch signalling between adjacent endothelial cells at the angiogenic front. In stable blood vessels, DII4 and Notch signalling (through receptors) maintains quiescent. VEGF activation increases expression of DII4. DII4 drives notch signalling, which inhibits the expression of VEGFR2 in the adjacent cell. The DII4-expressing tip acquire a motile, invasive and sprouting phenotype. Adjacent cells form the base of the emerging sprout.

Answer 202

Tissue macrophages have a role in carving out tunnels in ECM, providing avenues for capillary infiltration. Tissue-resident macrophages where shown to be associated with an angiogenic tip. The process of stabilisation also occurs with help from macrophages.

Answer 203

- when excessive: cancers, atherosclerosis, obesity | - when insufficient: baldness, ischaemia, limb fractures, theombosis

Answer 204

It is important to remember, angiogenesis is also a natural and healthy process involved in embryonic development, the menstrual cycle and wound healing.

Answer 205

Tumour growth is dependent on angiogenesis. Tumours less than 1mm^3 receive oxygen and nutrients through diffusion.

Answer 206

Larger tumours require new vessels, and so secrete VEGF. The subsequent new vessel also provides a route for metastasis.

Answer 207

1. Perivascular detachment and vessel dilation. 2. Onset of angiogenic sprouting 3. New vessel formation and maturation, recruitment of perivascular cells 4. Formation of tumour vasculature

Answer 208

Tumour blood vessels are irregularly shaped, dilated and tortuous. They are not organised into definitive venules, capillaries or arterioles. They also tend to be leaky and haemorrhagic, partly due to the overproduction of VEGF in comparison to relatively lower concentrations of inhibitors. Perivascular cells are only loosely associated.

Answer 209

Avastin is an anti-VEGF monoclonal antibody drug. It was first approved for advanced colon, lung, kidney and brain cancers. It does however produce a range of side-effects which includes: GI perforation, hypertension, proteinuria, venous thrombosis, haemorrhage, and wound healing complications.

Answer 210

New vessels at the base of atheromatous plaques can promote growth and rupture (however this is controversial). Overall, pro-angiogenic therapy is useful in cardiovascular disease to prevent tissue damage. Can also be used to improve tumour vasculature in order to increase cytotoxic drug delivery.

Answer 211

* Dietary – accounts for 40-45% of all cancers * Lifestyle – such as smoking and alcohol * Environmental – such as car exhaust fumes * Occupational – working in factories etc. * Medical – cytotoxic drugs in chemotherapy * Endogenous – chemicals generated in the body can also damage DNA

Answer 212

This can come from iatrogenic sources, from solar radiation, or even cosmic radiation.

Answer 213

1. DNA adducts - chemicals covalently boned to a base. 2. DNA alklyation 3. Base hydroxylation -resulting in bases not recognised 4. Abasic sites 5. Base dimers and chemical crosslinks 6. Double stranded breaks 7. Single stranded breaks

Answer 214

The toxic chemicals tend to be removed my mammalian metabolism – Type I followed by Type II metabolism.

Answer 215

Benzo[a]pyrene is a model compound to show how the product of a P450 reaction can be harmful. The molecule is a harmless polycyclic aromatic compound which is oxidised by P450 which adds an epoxide group to the molecule. The epoxide group is very electron deficient and so seeks out and reacts with DNA (a rich source of electrons, especially guanine). The epoxide group can be neutralised by an epoxide hydroxylase enzyme. If CYP450 epoxides faster than it can hydrolyse them, they can react with DNA resulting in electrophilic DNA adducts which causes DNA damage.

Answer 216

Aflatoxin is produced by Aspergillus flavus mold that grows on crops – commonly on poorly stored grains and peanuts. Aflatoxin B1 is a potent liver carcinogen as CYP450 enzyme generates a reactive epoxide (which this time is not a good substrate for epoxide hydroxylase) called Aflatoxin B1,2,3-epoxide. This attacks DNA in the liver causing liver cancer

Answer 217

2-napthylamine was a component of dyestuffs in the past, which was a potent human bladder carcinogen. In the liver, the molecule is glucoronidated and detoxicated. However, in the bladder with the presence of the acidic urine, the glucoronides are hydrolysed – liberating the reactive electrophile --> DNA adducts

Answer 218

Solar (UV) radiation causes the cross-linking of pyrimidine bases (especially thymine) causing pyrimidine dimers. The resulting mutation can lead to skin cancer.

Answer 219

Ionising radiation can generate free radicals in cells - especially oxygen free radicals such as superoxide and hydroxyl radicals. There possess unpaired electrons and thus seek out electron-rich DNA. Oxygen free radicals cause double and single stranded breaks, abasic sites, and other base modifications .

Answer 220

It is normally held inactive by MDM2, but is released by oxidative stress, nitric oxide, hypoxia, ribonucleotide depletion, mitotic apparatus dysfunction, oncogene activation, DNA replication stress, double-strand breaks and telomere erosion.

Answer 221

1. Direct reversal of DNA damage: - Photolase is an enzyme that splits pyrimidine dimers (caused by UV radiation) - Metyltransferases and Alkyltransferases remove alkyl groups from bases 2. Base excision repair (repairing abasic sites) is done by endonucleases to remove the nucleotide followed by a repair polymerase to refill the gap before DNA ligase re-joins the sugar backbone. 3. Nucleotide excision repair is used for bulky DNA adducts, where endonuclease and helicase enzymes remove a section of DNA before repair polymerases fills the gap once more. DNA ligase again seals the DNA backbone. 4. During/post-replication repair can be in form of base mismatch repair and recombinational repair (from breaks in DNA)

Answer 222

1. Structural alerts / SAR (Structural Activity Relationship) is where the chemical is looked at to see if it has a group known to damage DNA. 2. Bacterial gene mutation test (AMES) is done with S. typhimurium. 3. In-vitro mammalian cell assay – treat the cells with the chemical (mammalian cells with CYP450) and investigate for chromosomal abnormalities. 4. In-vitro micronucleus assay – cells are treated with the chemical and allowed to divide. However, cytokensis is blocked by cytochalasin-B so that binucleate cells are assessed for the presence of micronuclei. These occur when there is DNA damage. 5. In-vivo micronucleus assay

Answer 223

Bacterial gene mutation test (AMES) is done with S. typhimurium. The chemical to be tested in incubated with bacteria engineered to not produce histidine, along with mammalian CYP450 enzyme. If the chemical and/or its metabolites damage DNA, it will allow bacteria to produce histidine again. This means they will form colonies on histidine-free media. This is quantitative as the more bacteria on a plate, the more DNA damage the chemical causes.

Answer 224

- 4th most common cancer | - 2nd leading cause of cancer death

Answer 225

- Extraction of water from faeces (and electrolyte balance) - Faecal reservoir - Bacterial digestion (especially of vitamins such as vitamins B and K)

Answer 226

Goblet cells

Answer 227

Purple as they have a hyper chromic nucleus. They also tend to be disorganised and have mitotic figures.

Answer 228

2-5 million cells die per minute

Answer 229

A polyp is any projection from the mucosal surface into a hollow viscus

Answer 230

- hyperplastic - neoplastic (tend to be adenomas) - inflammatory - Juvenile Hamartoma - Peutz Jeghers Hamartoma - Lipoma

Answer 231

Hyperplastic polyps are quite common (90% of all polyps).

Answer 232

Adenomatous

Answer 233

- Age - First-degree relatives with colorectal carcinoma or adenocarcinoma - Specific mutations - Inflammatory diseases such as Ulcerative Colitis

Answer 234

1. Tubular (most common) - Composed of columnar cells with nuclear enlargement, elongation, multilayering and loss of polarity. There is increased proliferative activity and reduced differentiation. Architecture is dysplastic/disorganised. 2. Villous - Composed of mucinous cells organised in frond-like extensions 3. Tubulovillous [4. Flat and Serrated are other patterns.]

Answer 235

- enlarged - hyperchromasia - cigar shaped

Answer 236

Its ability to invade surrounding tissue. Specifically the muscularis mucosae (thin layer between mucosa and submucosa).

Answer 237

1. Extracellular matrix degradation (especially basement membrane) 2. Adhesion to degraded or new ECM 3. Ability to move into the new ECM

Answer 238

They are able to access the lymphatics and blood vessels easier.

Answer 239

Ulcerative colitis increases the risk of cancer as inflammation damages wall, which then requires greater proliferation and thus has a greater chance to acquire a mutation.

Answer 240

The adenoma-carcinoma sequence is the progression of an adenoma to a carcinoma accompanied by an increasing degree of genetic abnormalities. The accumulation of the mutations is more important than the order in which they occur. The major genetic abnormalities include the APC gene (at 5q location), K-Ras mutation (12p), SMAD loss, and P53 mutation/loss (17p location).

Answer 241

This is a result of a mutation of the Adenomatous Polyposis Coli (APC) gene [on chromosome 5q21]. In classical FAP syndrome, patients have up to 2500 adenoma polyps all over their colon but mostly on their descending colon. This greatly increases the risk of developing colonic carcinoma, so many patients have prophylactic colectomy by age 30. If left unmanaged, almost all patients will develop cancer by age 30.

Answer 242

Chromsome 5q21

Answer 243

HNPCC is an autosomal dominant familial syndrome where there are fewer adenomas than FAP (but again mainly at the left colon). In this case, the DNA mutation is at DNA repair genes leading to micro-satellite instability. Micro-satellites are repeat sequences prone to misalignment. Some micro-satellites are in coding sequences of genes which inhibit growth or apoptosis.

Answer 244

Mismatch repair genes which are mutated in HNPCC include MSH2, MLH1 and 4.

Answer 245

There is a higher incidence in the US, Eastern Europe and Australia and a lower incidence in Japan, Mexico and Africa.

Answer 246

- Low fibre - High fat - High red meat - Refined carbohydrates

Answer 247

heterocyclic amines are carcinogens found in red meat cooked at high temperatures.

Answer 248

- Vitamin C and E are ROS (oxygen radicals that damage DNA) scavengers - Isothyiocyanates are found in cruciferous vegetables (cauliflower, cabbage, broccoli). - Polyphenols found in green tea and fruit juices - Garlic is associated with apoptosis

Answer 249

- Altered bowel habits (constipation, diarrhoea, or a combination of the two) - Rectal bleeding - Tiredness and malaise due to iron deficiency - Discharge of mucus - Intermittent abdominal pain and cramps - Intermittent obstruction of colon leading to bloating - Constitutional weight loss and fatigue.

Answer 250

- rectosigmoid (55%) | - caecum/ascending colon (22%)

Answer 251

Because they produce vaguer symptoms, partly due to the capacity of the caecum to expand before getting blocked, and also they are more often mucinous and soft in nature so obstruction occurs later.

Answer 252

Diagnosis is usually done with the aid of radiology and a colonoscopy. As of yet, there are no reliable biomarkers for colon cancer, apart from advanced colorectal carcinoma.

Answer 253

Yes, all colorectal cancers are adenocarcinomas

Answer 254

Screening is the practice of investigating apparently healthy individuals with the object of detecting unrecognised disease or people with an exceptionally high risk of developing disease, and of intervening in ways that will prevent the occurrence of disease or improve the prognosis when it develops.

Answer 255

They are graded as well differentiated, moderately, or poorly differentiated.

Answer 256

Treatment for all stages is surgery. Chemotherapy and palliative options are available for later stages.

Answer 257

Pathological features associated with aggressive colorectal carcinoma include: - Greater depth of bowel wall penetration - Greater number of regional lymph nodes - Poor degree of differentiation - Venous or lymphatic invasion

Answer 258

- Basal cell carcinoma and Squamous cell carcinoma are from keratinocytes - Malignant melanoma are derived from melanocytes - Kaposi's sarcoma and angiosarcoma are derived from vascular tissue

Answer 259

Main causes of skin cancers are: - Genetic (rare) syndromes such as Gorlin’s syndrome and xeroderma pigmentosum - Viral infections such as HHV8 in Kaposi’s sarcoma and HPV in squamous cell carcinoma - UV light causes basal and squamous cell carcinoma, as well as malignant melanoma. Immunosuppression can also make you more susceptible to skin cancers. - Immunosupression

Answer 260

Basal Cell Carcinoma

Answer 261

- Generally seen in elderly, but also teens with recreational sun exposure - Derived from pluripotent stem cells - Most commonly found in sun-exposed areas - Locally destructive but usually NOT metastatic

Answer 262

Squamous cell carcinomas are also tumours of the elderly due to lifelong sun exposure, therefore appearing commonly in sun exposed areas. They develop from damaged basal keratinocytes (stem cells). Unlike basal cell carcinomas, squamous cell carcinomas can often metastasise to regional lymph nodes the to solid organs such as the lungs.

Answer 263

- Young adults - Light-skinned people - Previous sun burns before age of 15

Answer 264

They are tumours arising from epidermal melanocytes (but also sometimes from dermal melanocytes). It is strongly associated with intermittent sun exposure. This type of skin cancer is highly metastatic and aggressive, spreading to regional lymph nodes before solid organs, often the lungs, liver and brain.

Answer 265

1. Superficial spreading melanoma – There is an initial horizontal growth phase, from which the cancer can usually be removed, followed by a vertical growth phase (and into lymphatics and vasculature). 2. Nodular melanoma – this is when the melanoma has little or no horizontal growth phase, just a vertical growth phase. This sub-type of melanoma is the most aggressive and always has a poor prognosis. 3. Lentigo maligna melanoma – usually affect the elderly and develop from lentigo maligna also known as melanoma in situ. Lentigo maligna is due to proliferation of malignant melanocytes within the epidermis, with no metastasis. It usually has an irregular shape, with light and dark brown colours with a size usually bigger than 2cm. 4. Acral lantiginous melanoma – starts on the feet and hands as pigmented streaks. Tends to be related to trauma rather than sun exposure. It is most common in Afrocarribeans.

Answer 266

Amelanotic melanoma

Answer 267

ABCD: Asymmetry, Border, Colour and Diameter

Answer 268

- Family history of dysplastic neavi or melanoma - UV irradiation - Sunburns below the age of 15 - Intermittent burn exposure to fair skin - Atypical/dysplastic nevus syndrome - Personal history of melanoma - Skin types I and II

Answer 269

UV-C [100-280 nm] UV-B [280-310 nm] UV-A [310-400 nm]

Answer 270

- UV-B rays directly induces abnormalities in DNA. It affects pyrimidines (cytosine and thymine) creating dimers. Thymine dimers are the most commonly detected in UV-B irradiated DNA. - UV-A also promotes skin carcinogenesis by creating cyclobutane butane pyrimidine dimers - Photon energy can also create oxygen free radicals which can cause oxidative damage to DNA

Answer 271

The pyrimidine dimers are usually repaired quickly by the process of nucleotide excision repair.

Answer 272

Xeroderma pigemntosum

Answer 273

- Increased expression of down-regulatory cytokines such as IL1-Ra which suppresses Langerhan cell activity - Inhibits expression of ICAM-1 (Inflammatory Cell Adhesion Molecule 1) which decreases migration of T-cells to the skin - Depletes the number of Langerhans cells which decreases epidermal immunosurvailance

Answer 274

Basal layer of epidermis

Answer 275

The amount and type of MELANIN. NOT the number of melanocytes This is determined by the MCR1 receptor.

Answer 276

36 - forming an epidermal melanin unit.

Answer 277

Melanin is transferred to the keratinocytes, packed in melanosomes and delivered via dendritic tips which are phagocytosed by the keratinocyte.

Answer 278

- Eumelanin – brown/black and insoluble. It shields keratinocyte nuclei from UV rays by absorbing UV - Pheromelanin – yellowish/brown and soluble in alkalis.

Answer 279

Melanocortins (from POMC) binding to types of Melanocortin Receptors (20 types of MCR1)

Answer 280

P53 mediates growth arrested in G1, to allow DNA repair or apoptosis of the cell. Mutation of the p53 allele due to UV exposure will lead to production of mutated p53 and inactivation of wild-type p53. Subsequent failure of p53 to arrest cell division allows the daughter cells to acquire mutations.

Answer 281

In renal transplant recipients (drug induced immunosuppression), squamous cell carcinoma are 10 times more common than basal cell carcinoma. EV–HPV types have been identified from squamous cell carcinomas.

Answer 282

incidence is increasing | mortality is decreasing

Answer 283

mortality is decreasing mainly due to effective hormone therapies, but also earlier and more self diagnosis, as well as more effective chemo/radiotherapies.

Answer 284

through infantile growth, puberty, pregnancy, lactation, weaning and postmenopausal regression.

Answer 285

Breast carcinoma is a tumour of the epithelial cells which line the acini and ducts.

Answer 286

Even though only the luminal epithelial cells have oestrogen receptors, they will stimulate other cells (Myopeithelial cells) in the mammary gland to grow through paracrine effects.

Answer 287

* Lobular carcinoma – we can see rudimentary tubules etc. So still differentiated * Infiltrating ductal carcinoma (also simply breast carcinoma) – does not show these tubules, and is less differentiated than lobular carcinomas. They have no special type of histological structure. These are the vast majority of breast cancers (80%). * Medullary carcinoma – does not show many signs that it is from breast tissue. The cells are packed with vesicles containing neuropeptides and growth factors, very undifferentiated.

Answer 288

Immunohistochemical staining

Answer 289

Important risk factors associated with breast cancer are to do with lifetime exposure to oestrogen: • Age of onset of periods • Age of first full-time pregnancy (pregnancy is protective) • Some contraceptive pills • Some hormone replacement therapies. • Obesity • Diet, physical activity, height, medication.

Answer 290

The oestrogen receptor is a cytosolic protein (not in the membrane) that normally exists as a monomer bound to hsp90 (heat-shock protein). Once in the cytoplasm, the oestrogen molecule is able to displace the hsp90 chaperone molecule and bind to the receptor. This then allows the oestrogen receptor to dimerise with another ER. The dimerised protein enters the nucleus (with oestrogen still bound) to act as a transcription factor.

Answer 291

Oestrogen Responsive Elements

Answer 292

- Progesterone receptor - Cyclin D1 – regulator of cell cycle - C-myc – regulator of apoptosis - TGF-α – a growth factor.

Answer 293

This can be done by ovarian suppression, blocking oestrogen production (for example by inhibiting aromatase) or inhibiting oestrogen responses.

Answer 294

- oophorectomy - ovarian irradiation - LHRH AGONists

Answer 295

Goserelin, Buserelin, Leuprolide and Triptorelin

Answer 296

Anti-oestrogen drugs are compounds with a similar structure to oestrogen. They bind strongly to the ER, blocking their activity as transcription factors (and therefore blocking stimulation of cancer, causing the cell to be held at the G1 phase of the cell cycle). These drugs are as effective in post-menopausal women as in pre-menopausal women.

Answer 297

Tamoxifen Toremifene ICI 182780 Baloxifene

Answer 298

Tamoxifen has beneficial oestrogenic properties such as: - Oestrogenic effects in bone, and therefore protecting against osteoporosis - Oestrogenic effects in the cardiovascular system – lowering LDLs and increasing HDLs Undesirable oestrogenic effects of Tamoxifen include: - Promoting endometrial cancer, fibroids, polyps, and vaginal discharge. - Associated with thromboembolic episodes such as DVT and stroke. - Increases cataracts, and vasomotor symptoms.

Answer 299

- prevents growth of tumour so that it can be removed by surgery - reduces incidence of contralateral breast cancer by 1/3

Answer 300

The conversion of androstenedione (and to a lesser extent testosterone) to oestrone to osteradiol.

Answer 301

Aromatase (a complex consisting CYP450)

Answer 302

- CYP450 | - Steroid sulphatase

Answer 303

A lot of oestrogen is sulphated before it is exported, to oestrone sulphate by steroid sulphatase.

Answer 304

- Type I are suicide inhibitors. When the enzyme acts on these inhibitors, they yield a reactive alkylating species, permanently inactivating the enzyme (think of suicide bombers). Exemestane is such a inhibitor. - Type II are simply competitive inhibitors. Anastrozole is such a drug.

Answer 305

We can also use progesterone agonists (over-stimulation) in the treatment of uterine and breast cancer with clinically proven antineoplastic properties. Progestin therapy for metastatic breast cancer has been used principally as a second or third line therapy following SERMs.

Answer 306

A significant proportion of patients presenting with breast cancer and, all patients with metastatic disease become resistant to endocrine therapies.

Answer 307

Leukaemia results from a series of mutations in a single lymphoid or myeloid stem cell (sometimes even haematopoietic stem cell). The mutations lead the progeny of that cell to show abnormalities in proliferation, differentiation and cell survival, leading to the steady expansion of the leukaemic clone.

Answer 308

Leukaemia is different to most cancers, as it is not usually associated with solid tumours.

Answer 309

- replacing cells in normal bone marrow - circulating free in blood - invading tissue

Answer 310

- Mutation in known proto-oncogene - Loss of function of TS gene - Creation of a novel chimeric or fusion gene - Deregulation of gene when translocation brings it under the influence of a promoter of another gene - mutations that result in increase tendency of chromosomal breaks - if the cell cannot repair DNA normally - Inherited of other constitutional abnormalities for example Down's syndome

Answer 311

- irradiation - anti-cancer drugs - cigarette smoking and other carcinogenic chemicals such as benzene

Answer 312

Because leukaemia is cancer of the cells that normally travel around the body and enter tissues/

Answer 313

- Leukaemias that behave in a relatively benign way are called CHRONIC. They cause less impairment of function of normal tissues, but will still cause death in a number of years. - Leukaemias that behave in a relatively malignant manner are called ACUTE. If not treated, the disease is very aggressive and will lead to death quickly.

Answer 314

- Chronic myeloid leukaemia - Chronic lymphocytic leukaemia - Acute myeloid leukaemia - Acute lymphoblastic leukaemia

Answer 315

- cells continue to proliferate, but no longer mature. This means there is a build-up of the most immature cells – the myeloblasts. - These ‘blast cells’ are found built up in the bone marrow as well as circulating. - There is also a failure of production of normal functioning end cells such as neutrophils, monocytes, erythrocytes etc - decreased platelets because of decreased megakaryocytic production and increased platelet consumption

Answer 316

Acute: The mutations are usually of transcription factors, so the transcription of multiple genes are affected. This leads to a more profound disturbance in cell behaviour. Chronic: The mutations are usually of signalling pathways. This has more of an affect on cell survival, with function not seriously affected.

Answer 317

In AML there is a failure of production of end cells, while in CML there increased production of end cells.

Answer 318

Like AML, acute lymphoblastic leukaemia has a marked increase in very immature cells – lymphoblasts. This is accompanied by a failure to produce T or B lymphocytes or natural killer cells. Whereas in chronic lymphocytic leukaemia there is an increase in abnormal T or B lymphocytes.

Answer 319

1. Accumulation of abnormal cells 2. Metabolic effects of leukaemic cell proliferation 3. Crowding of normal cells 4. Loss of immune function

Answer 320

- Leukocytosis --> increased viscosity of blood -- CVD - Bone pain (in acute leukaemia) - Hepatomegaly and splenomegaly - Lymphadenopathy - Thymic enlargement - Skin infiltration producing small tumours

Answer 321

- Hyperuricaemia due to increased rate of DNA breakdown rate of uric acid production increases. Uric acid can be crystalised and deposit in the kidneys leading to kidney failure. In chronic leukaemias uric acid in tissues can cause gout - Hypermetabolism symptoms due to increased metabolic rate of leukaemic cells. These include weight loss, low grade fever, and increased sweating.

Answer 322

loss of function of bone marrow as a result of leukaemic replacement. Leads to anaemia, neutropenia, and thrombocytopenia.

Answer 323

ALL can be of B-lineage (about ¾ of cases) or T-lineage (about ¼ of cases)

Answer 324

15-24 year olds

Answer 325

2-5 year olds. However, there is a gradual increase of incidence after age 50 due to a genetic subset of ALL which occurs in older adults.

Answer 326

Nothing is known about the cause of T-lineage ALL, but a little is known about the cause of B-lineage ALL. Epidemiological studies suggest that B-lineage ALL results from delayed exposure to a common pathogen.

Answer 327

- Bone pain due to proliferation in the bone marrow - Hepatomegaly and splenomegaly - Lymphadenopathy – enlarged lymph nodes. These are commonly in the cervical, axillary and inguinal region. - Thymic enlargement (only if T-lineage) - Testicular enlargement due to leukaemic infiltration of the testes - Cranial nerve palsies due to meningeal infiltration - Renal enlargement - Hyperuricaemia - Anaemia – fatigue, lethargy, pallor and breathlessness - Neutropenia – fever and other features of infection - Thrombocytopenia – bruising, purpura and bleeding into subcutaneous tissue

Answer 328

- blood count - blood film - followed by liver and renal function test - bone marrow aspirate - chest x-ray to show thymic enlargement

Answer 329

An ALL blood film will show large lymphocytes, high nucleo-cytoplasmic ratio and diffuse chromatin pattern.

Answer 330

immunophenotyping (using fluorescently labelled antibodies to detect the expression of antigens on surface of leukaemic cells) can be used to determine if the ALL is of B or T-lineage.

Answer 331

different genetic subtypes have different prognosis and different management strategies.

Answer 332

Treatment for ALL is supportive (red cells, platelets and antibiotics), systemic chemotherapy and intrathecal chemotherapy. In poor prognosis cases, a bone marrow transplant may be needed. ¾ of ALL cases can be cured!

Answer 333

- Translocation between chromosome 12 and 21 forming fusion gene ETV6-RUNX1 - Dysregulation of a proto-oncogene by juxtaposition to it by a promoter region of another gene. For example in t(10;14)(q24;q11)—the TCL3 gene is dysregulated by proximity to the TCRA gene. - Point mutation in proto-oncogene