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Cancer Flashcards

1
Q

Define metaplasia.

A
  • a reversible change in which one adult cell type (usually epithelial) is replaced by another adult cell type -> this process is reversible
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2
Q

Give an example of a pathological metaplasia.

A
  • gastro-oesophageal reflux causes the oesophageal epithelium to change from squamous to columnar -> Barrett’s oesophagus
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3
Q

Give an example of a physiological metaplasia.

A
  • in pregnancy the cervix opens up and the columnar epithelium of the endocervical canal is exposed to the acidic uterine fluids making it become squamous -> when the cervix closes up again, the cell type changes back to normal
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4
Q

Define dysplasia.

A
  • abnormal pattern of growth in which some cellular and architectural features of malignancy are present with an intact basement membrane and without showing an invasion
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5
Q

What are the features of dysplasia?

A
  • INCREASED NUCLEO-CYTOPLASMIC RATIO
  • loss of architectural orientation
  • loss in uniformity of individual cells (pleomorphism)
  • nuclei which have become hyperchromatic and enlarged
  • abundant, abnormal, mitosis
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6
Q

In what sites is dyplasia common?

A
  • cervix -> HPV infection
  • bronchus -> smoking (pseudostratified columnar -> squamous)
  • colon -> UC associated with IBD (UC -> dysplasia -> cancer)
  • larynx -> smoking
  • stomach -> pernicious anaemia (chronic stomach inflammation)
  • oesophagus -> acid reflux (Barrett’s oesophagus)
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7
Q

What is the difference between the grades of dysplasia?

A
  • low grade = unlikely to become cancer
  • high grade = likely to become cancer -> further changes -> darker due to higher nucleo-cytoplasmic ratio
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8
Q

Define malignancy.

A
  • an abnormal, autonomous proliferation of cells unresponsive to normal growth control mechanisms
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9
Q

Define neoplasia.

A
  • any new growth, benign or malignant
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10
Q

What are the features of a benign tumour?

A
  • do not invade -> do not metastasise
  • encapsulated
  • usually well differentiated
  • slowly growing
  • normal mitoses
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11
Q

When can benign tumours be dangerous?

A
  • in a dangerous place -> a benign tumour in the meninges or pituitary
  • secretes something dangerous- > insulinoma
  • becomes infected
  • causes haemorrhage
  • it ruptures -> liver adenoma can cause massive haemoperitoneum
  • torsion leads to ischaemic necrosis
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12
Q

What are the features of a malignant tumour?

A
  • invade surrounding tissues
  • metastasise
  • have no capsule
  • poorly differentiated
  • rapidly growing
  • abnormal mitoses
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13
Q

Define metastasis.

A
  • a discontinuous growing colony of tumour cells, at some distance from the primary cancer
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14
Q

What staging system is used for colon cancer?

A

o Dukes

o Dukes A = growth limited to wall (nodes negative) -> 90-98% survival

o Dukes B = growth beyond muscularis propria (nodes negative) -> 70&

o Dukes C1 = nodes positive (apical lymph node negative)

o Dukes C2 = apical lymph node is positive -> 30-40% survival

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15
Q

Benign and malignant tumours are distinguished from each other by all of the following except:

  1. Degree of differentiation
  2. Speed of growth
  3. Capsulation
  4. Invasiveness
  5. Site
A
  • 5
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16
Q

Well differentiated tumours are characterised by all of the following, except:

  1. A small numbers of mitoses.
  2. Lack of nuclear pleomorphism
  3. A high nuclear-cytoplasmic ratio.
  4. Relatively uniform nuclei
  5. Close resemblance to the corresponding normal tissue
A
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17
Q

What types of benign epithelial tumours are there?

A
  • papiloma -> occur on the surface of epithelium -> skin, bladder
  • adenoma -> occur on glandular epithelium -> stomack, thyroid, colon, kidney, pituitary, pancreas
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18
Q

What is a carcinoma?

A
  • a malignant tumour derived from epithelium
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19
Q

What types of carcinomas exist?

A
  • squamous cell (if from skin/oesophagus)
  • adenocarcinoma (if from glandular epithelium)
  • transitional cell (if from transitional epithelium)
  • basal cell carcinoma
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20
Q

What are sarcomas?

A
  • malignant tumours dervied from connective tissue cells (soft tissue)
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21
Q

What are the different types of sarcomas?

A
  • fat - liposarcoma
  • bone = osteosarcoma
  • cartilage = chondrosarcoma
  • striated muscle = rhabdomyosarcoma
  • smooth muscle = leiomyosarcoma
  • nerve sheath = malignant peripheral nerve sheath tumour
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22
Q

Define leukaemia.

A
  • a malignant tumour of bone marrow derived cells which circulate in blood (seen in blood)
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23
Q

Define lymphoma.

A
  • a malignant tumour of lymphocytes (usually) in lymph nodes (seen in lymph nodes)
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24
Q

Define teratoma.

A
  • a tumour derived from germ cells, which have the potential to develop into tumours of all three germ cell layers
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25
Q

What are the three germ cell layers?

A
  1. ectoderm
  2. mesoderm
  3. endoderm
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26
Q

What is the difference between gonaldal teratomas in males and females?

A
  • males = almost always malignant
  • females = alsmost always benign
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27
Q

What are harartomas?

A
  • 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
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28
Q

A benign tumour of glandular tissue is:

  1. an adenoma
  2. a leiomyoma
  3. an adenocarcinoma
  4. a squamous papilloma
  5. a lymphoma
A
  • 1
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29
Q

A malignant tumour derived from soft tissue is a:

  1. Carcinoma
  2. Sarcoma
  3. Teratoma
  4. Lymphoma
  5. Melanoma
A
  • 2
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30
Q

What grading system is used for breast cancer?

A
  • Nottingham scoring system
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31
Q

What grading system is used forprostate cancer?

A
  • Gleason
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32
Q

Define anaplastic.

A
  • 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
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33
Q

What is tumour grading?

A
  • the degree of differentiation -> higher grade = poor differentiation
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34
Q

What is tumour staging?

A
  • how far a tumoru has spead -> higher stage = greater spread
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35
Q

Which is more important stage or grade?

A
  • stage
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36
Q

Briefly summarise the cell cycle.

A
  • 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
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37
Q

What do proto-oncogenes do?

A
  • code for proteins involved in maintenance of cell growth, division and differentiation
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38
Q

What can happen with mutation to proto-oncogenes?

A
  • 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
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39
Q

Name 4 different mechanism which can lead to oncogene formation.

A
  • mutation in the coding sequence
  • gene amplification
  • chromosomal translocation -> leading to chiamaeric genes
  • insertional mutagenesis -> viral infection
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40
Q

Describe a chromosomal translocation leading to cancer.

A
  • 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)
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41
Q

What is the mechanism of RAS?

A
  • 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

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42
Q

What process fails in the presence of mutant RAS?

A
  • 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
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43
Q

Which one of the following statements is incorrect?

a. mutation can convert a protooncogene to an oncogene
b. gene amplification of a protooncogene can be oncogenic
c. chromosome translocation can lead to inappropriate expression of a protooncogene and to an oncogenic effect
d. a protooncogene can be activated to an oncogene by insertional mutagenesis
e. protooncogenes are not expressed in normal cells

A
  • e
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44
Q

What is the the pathway in which RAS is involved?

A
  • 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
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45
Q

How many copies of proto-oncogenes have to become mutated for it cause cancer?

A
  • only one, the other copy will be insufficient to stop its effects
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46
Q

What are the function classes of proto-oncogenes?

A
  • growth factors
  • growth factor receptors
  • intracellular transducers (signalling proteins)
  • intracellular receptors
  • transcription factors
  • cell cycle regulatory proteins
  • cell death regulators
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47
Q

What are tumour suppressor genes?

A
  • 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
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48
Q

How many copies of tumour suppressor genes must be mutated for it to cause cancer?

A
  • both = two hit hypothesis
  • an exception is p53because the mutated gene become dominant
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49
Q

What are the features of inherited cancer suspectibility?

A
  • 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
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50
Q

Describe retinoblastoma.

A
  • is a malignant cancer of developing retinal cells
  • sporadic disease usually involves one eye
  • hereditary causes can be unilateral or bilateral and multifocal
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51
Q

What causes retinoblastoma?

A
  • 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
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52
Q

What is the treatment of retinoblastoma?

A
  • 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
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53
Q

What are the functions of p53?

A
  • metabolic homeostais
  • anti-oxidant defence
  • DNA repair
  • growth arrest
  • senescence
  • apoptosis in worst case
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54
Q

What activates p53?

A
  • stress or DNA damage causes p53 to be released from Mdm2
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55
Q

What is APC tumour suppressor gene involved in?

A
  • cell adhesion and signalling -> involved in WNT pathway -> binds to beta-catenin and inhibits its drive for proliferation
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56
Q

What will patients suffering from mutation in both APC genes develop?

A
  • hyperproliferative state of colonic cells -> polps of the colon will appear -> THIS IS NOT CANCER
  • 90% risk of developing colorectal carcinoma
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57
Q

What is the treatment for people with two mutated APC genes?

A
  • removal of their colons in their 20s
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58
Q

The protein products of tumour suppressor genes are not NOT involved with:

a. regulation of cellular proliferation
b. metabolism of drugs
c. regulation of cell cycle
d. repair of DNA damage
e. control of transcription

A
  • b
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59
Q

What factors influence the rate that cells divides at?

A
  • 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
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60
Q

Define contact inhibition of growth.

A
  • 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
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61
Q

When are cells most vunerable?

A
  • during mitosis
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62
Q

Why are cells most vunerable during mitosis?

A
  • 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
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63
Q

What happens in the S-phase of the cell cycle?

A

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
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64
Q

Describe the structure of centrosomes.

A
  • 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
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65
Q

State the 2 functions of the centrosome.

A
  • microtubule organising centre (MTOC) -> controls the polymerisation of microtubules
  • co-ordinate the mitotic spindle
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66
Q

What are the phases of the mitosis?

A
  • prophase
  • prometaphase
  • metaphase
  • anaphase
  • telophase
  • cytokinesis
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67
Q

What occurs in prohase?

A
  • condensation of chromatin
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68
Q

Explain the process of chromatin condensation.

A
  • 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
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69
Q

What are kinetochore?

A
  • a complex of proteins that are a key regulator of the processes around chromosomes in the cell cycle
  • surround the centromere of chromosomes
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70
Q

What processes are happening in late prophase?

A
  • 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
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71
Q

What are the 2 types of microtubules?

A
  • radial microtubule arrays
  • polar microtubules
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72
Q

What are radial microtubule arrays?

A
  • 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
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73
Q

What are polar microtubules?

A
  • when two radial arrays from two centrosomes meet in the middle they are referred to as polar microtubules
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74
Q

What occurs in early prometaphase?

A
  • breakdown of nuclear membrane is finalised
  • spindle formation is largely complete
  • attachment of chromosomes to spindle via kinetochores
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75
Q

What occurs in lae prometaphase?

A
  • microtubule from opposite pole is captured by sister kinetochore -> chromosomes attached to each pole congress to the middle via the microtubules
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76
Q

What is CENP-E?

A
  • CENP-E is a centromere protein E (kinetochore tension sensing) -> senses whether the kinetochore is attached to microtubules or not
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77
Q

What is metaphase?

A
  • the point/stage at which chromosomes have aligned at the equator of the spindle fibres
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78
Q

What are the overall actions of anaphase?

A
  • paired chromatids separate to form 2 daughter chromosomes
  • can be split into anaphase A and anaphase B
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79
Q

What is cohesin?

A
  • a protein complex that holds the sister chromatids tightly bound together -> acts as a glue
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80
Q

What occurs in anaphase A?

A
  • cohesin is broken down and the microtubules get shorter -> daughter chromatids start moving towards opposite spindle poles
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81
Q

What occurs in anaphase B?

A

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

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82
Q

What happens in telophase?

A
  • 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
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83
Q

Describe the process of cytokinesis.

A
  • 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
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84
Q

How does kinetochore act as a checkpoint?

A
  • 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
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85
Q

How does BUB protein kinase function?

A
  • BUBs dissociate from the kinetochore when chromatids are properly attached to the spindle -> when all dissociated, they go on to signal progression to anaphase
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86
Q

What is amphelic attachment?

A
  • 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
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87
Q

What is syntelic attachment?

A
  • 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
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88
Q

What is merotelic attachment?

A
  • 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
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89
Q

What is monotelic attachment?

A
  • 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
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90
Q

What are the two major routes to aneuploidy?

A
  • mis-attachment of microtubules to kinetochores
  • aberrant centrosome
  • aberrant DNA duplication
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91
Q

How can aberrant centrosomes lead to aneuploidy?

A
  • 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
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92
Q

How can aberrant DNA duplication lead to aneuploidy

A
  • 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
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93
Q

How does checkpoint kinase work as an anti-cancer drug?

A
  • 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
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94
Q

How do texanes and vinca alkaloids work as cancer treatments?

A
  • alter microtubule dynamics -> produce unattached kinetochores -> causes long-term mitotic arrest
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95
Q

What cancers can be treated with texanes and vinca alkaloids?

A
  • breast
  • ovarian
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96
Q

What happens to cells if something goes wrong during the cell cycle?

A
  • 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
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97
Q

At what point are there cell cycle checkpoints?

A
  • 1st checkpoint is during G1
  • 2nd is just before mitosis -> checks for DNA damage before entering mitosis (G2)
  • 3rd is a metaphase-anaphase checkpoint
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98
Q

How do tumour cells by pass cell cycle checkpoints?

A
  • 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
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99
Q

What processes occur during the signal cascade?

A
  • response to extracellular factors
  • signal amplification
  • signal integration
  • modulation by other pathways
  • regulation of divergent responses
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100
Q

State 2 molecules which activates receptor protein tryosine kinase (RPTK)?

A
  • epidermal growth factor (EGF)
  • platelet derived growth factor (PDGF)
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101
Q

Explain the mechanism of activation of receptor protein tryosine kinase?

A
  • 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
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102
Q

Describe the kinase cascade.

A
  • 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…
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103
Q

What is c-Myc?

A
  • a transcription factor - controls the expression of other genes
  • is a proto-oncogene -> overly expressed in a lot of tumours
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104
Q

What are the 3 key components of the signalling pathway?

A
  • regulation of enzyme activity by protein phosphorylation (kinases)
  • adapter proteins
  • regulation by GTP-binding proteins
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105
Q

What is herceptin?

A
  • an antibody that inhibits HER2 receptor tryosine kinase
  • important in a number of tumours including breast cancer where is it overly expressed
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106
Q

What is the treatment for HER2-positive metastatic breast cancer?

A
  • anti-HER2 antibodies -> blocks the early stages of growth stimulation
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107
Q

Describe adaptor proteins.

A
  • 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
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108
Q

What is Grb2?

A
  • 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
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109
Q

What are the 2 most common oncogenic mutations of Ras?

A
  • V12Ras -> glycine residue in position 12 of Ras protein is changed to valine
  • L61Ras -> glutamine in position 61 in converted to leucine
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110
Q

Why is V12Ras oncogenic?

A
  • 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
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111
Q

Why is L61Ras oncogenic?

A
  • 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
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112
Q

What is the first kinase in the kinase cascade, plus name a common oncogenic mutation of the enzyme?

A
  • Raf
  • B-Raf is a common mutation in melanomas -> can be be inhibited for a while until the tumour takes over
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113
Q

What is the overall end product of the kinase cascade?

A
  • 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
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114
Q

What activates cyclin-dependent kinases?

A
  • 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
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115
Q

Describe cyclin-dependent kinases.

A
  • 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
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116
Q

What does CDK1 do?

A
  • binds to cyclin B to phophorylate substrates at mitosis -> breaks down the nuclear envelope
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117
Q

What does does CDK2 do?

A
  • binds to cyclin E -> active kinase will be phosphorylated at the start of synthesis
  • a tumour suppressor that is inactivated in many cancers
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118
Q

What is the overall mechanism which activates CDK1?

A
  • 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
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119
Q

Describe the metaphase-anaphase checkpoint.

A
  • 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
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120
Q

What CDKs and cyclins control the G1 phase of the cell cycle?

A
  • GDK2 and cyclin E
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121
Q

What CDKs and cyclins control the S phase of the cell cycle?

A
  • CDK2 and cyclin E
  • CDK2 and cyclin A
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122
Q

What CDKs and cyclins control the M phase of the cell cycle?

A
  • CDK1 and cyclin B
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123
Q

How do cyclins affect CDKs?

A
  • 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
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124
Q

What is retinoblastoma?

A
  • a key protein in regualting the cell cycle -> is present throughout the cell cycle

o IS A TUMOUR SUPPRESSOR GENE

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125
Q

What is the mechanims of retinoblastoma?

A
  • 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
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126
Q

What actives the CDK4/6-cyclin D kinase complex?

A
  • c-Myc induction
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127
Q

Name a target for E2F TFs.

A
  • cyclin E -> next cyclin required for cell cycle progression
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128
Q

How do CDK kinase inhibitors regulate CDKs?

A

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

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129
Q

Describe the chain of CDK-cyclin complexes reuired throughout the cell cycle.

A
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130
Q

What can damage DNA?

A

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

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131
Q

How is DNA damaged by carcinogens?

A
  • base dimers and chemical cross-links
  • base hydroxylations
  • abasic sites
  • single strand breaks
  • double strand breaks
  • DNA adducts and alkylation
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132
Q

What are base dimers and chemical cross-links?

A
  • where DNA molecules are chemically linked up
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133
Q

What are abasic sites?

A
  • 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
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134
Q

What are DNA adducts and alkylations?

A
  • 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
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135
Q

What group of molecules does the body often metabolise into carcinogens?

A

o polycyclic aromatic hydrocarbons

  • common environmental pollutants, formed from combustion of fossil feusl and tobacco
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136
Q

How does the body metabolise benzo[a]pyrene?

A

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
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137
Q

How is benzo[a]pyrene a carcinogen?

A
  • 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
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138
Q

What is aflatoxin B1?

A
  • a very potent human liver carcinogen formed by aspergillus flavus mould
  • common on poorly stored grains/peanuts -> especially common in Africa and Far-East
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139
Q

How is aflatoxin a carcinogen?

A
  • 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
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140
Q

What is 2-naphthylamine?

A
  • a potent bladder carcinogen
  • used to be used in dye industry but it is now very uncommon to come into contact with it
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141
Q

How is 2-napthylamine metabolised into a carcinogen?

A
  • 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
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142
Q

How can solar/UV radiation cause (skin) cancer?

A

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
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143
Q

How can ionising radiation bring about mutations?

A
  • cause the formation of oxygen free radicals -> very potent electrophiles
  • usually either super oxide radicals or hydroxyl radicals
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144
Q

How do oxygen free radicals cause mutations in/on DNA?

A

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)

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145
Q

What enzyme system is most frequently involved in the activation of chemicals to metabolites that can damage DNA?

a. glucuronyl transferase
b. haem oxygenase
c. cytochrome P450
d. xanthine oxidase
e. glutathione transferase

A

c. cytochrome P450

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146
Q

What is p53 tied up with when unactivated?

A
  • Mdm2
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147
Q

What causes the uncoupling of Mdm2 and p53?

A

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
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148
Q

What is the action of p53?

A
  • 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
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149
Q

What are the 4 types of DNA repair?

A
  1. direct reversal of DNA damage
  2. base excision repair
  3. nucleotide excision repair
  4. during or post replication repair
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150
Q

Describe the repair mechanism called direct reversal of DNA damage.

A
  • photolyase splits cyclobutane pyrimidine-dimers formed from UV light to recover the pyrimidines
  • methyltransferases and alkyltransferases remove alkyl groups from DNA bases
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151
Q

Describe base excision repair.

A
  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
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152
Q

Describe nucleotide excision repair.

A
  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
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153
Q

Which of the following is involved in the repair of damaged DNA?

a. mutation
b. epoxidation
c. DNA adduction
d. base excision repair
e. sister chromatid exchange

A

d. base excision repair

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154
Q

Which base is at most risk to damage?

A
  • guanine and the adenine
  • are the most electron-rich molecules -> most susceptible to electrophile damage
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155
Q

Define Cell Bahviour.

A
  • term used to describe the way cells interact with their external environment and their reactions to this, particularly proliferative and motile responses of cells
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156
Q

What external influences do cells detect?

A
  • 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)
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157
Q

What external factors can influence cell divison?

A
  • growth factors
  • cell-cell adhesion
  • cell-ECM adhesion
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158
Q

In what situation must cells be in for them to react to growth factors?

A
  • cell require to be bound to an extracellular matrix to be reactive to soluble growth factors and therefore proliferate
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159
Q

What is anchorage dependence?

A
  • attachment to the ECM may be reuired for cell survival
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160
Q

How do cells adhere to the ECM?

A
  • 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
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161
Q

What are integrins?

A
  • 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
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162
Q

How do integrins bind to the ECM?

A
  • 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
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163
Q

What does the a5b1 fibronectin receptor bind to?

A
  • binds to arg-gly-asp (RGD)
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164
Q

Which is the only integrin known that doesn’t associate with the actin cytoskeleton?

A
  • a6b4 integrin complex found in epithelial hemidesmosomes are linked to the cytokeratin
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165
Q

How do cell signal to and from the ECM?

A
  • 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
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166
Q

What is “outside-in” integrin signalling?

A

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
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167
Q

How do integrins promote signalling and actin assembly?

A
  • 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
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168
Q

What is “inside-out” signalling?

A
  • 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
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169
Q

Give some example where inside-out integrin signalling occurs.

A
  • inflammation or blood clotting
  • switching on adhesion of circulating leukocytes
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170
Q

Describe the conformation of integrins and how it affects binding?

A
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171
Q

What is density-dependence of cell division?

A
  • competition for growth factor occurs -> the hihger the density the greater the growth factor -> slower metabolism and division
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172
Q

What signals are required for proliferation of tissue cells?

A
  • 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

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173
Q

What is contact inhibiton of locomotion?

A
  • 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
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174
Q

What does contact of epithelial cells lead to?

A
  • mutual induction of spreading to create a stable monolayer
  • total spread of contacted cells is greater than that of non-contacted
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175
Q

What are cell-cell junctions dependent on?

176
Q

What happens to the rate of proliferation when there aren’t any cell-cell junctions?

A
  • 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
177
Q

Is beta-catenin the link between cell-cell adhesion and proliferation?

A
  • 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
178
Q

What is the main mechanism for contact inhibition of proliferation?

A
  • 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
179
Q

What are some minor adhesion-associated signalling pathways are known to influence contact-induced inhibition of proliferation?

A
  • 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
180
Q

What happens if cells lose their behavioural restraints?

A
  • 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
181
Q

Other than promoting the formation of solid tumours, what is an important consequence of loss of contact inhibition of locomotion for the progression of cancer?

A
  • allows the invasion of cells -> won’t be inhibited by the contact
182
Q

How does a primary carcinoma cell metastasise?

A
  • 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
183
Q

State three physiological occassions where aniogenesis is vital?

A
  • embryonic development
  • wound healing
  • menstraul cycle
184
Q

Name some diseases caused by insufficient angiogenesis.

A
  • baldness
  • ischaemia -> MI, stroke
  • limb fractures
  • thrombosis
185
Q

Name some disease caused by vascular malformations.

A
  • angiodysplasia -> HHT and VWD
  • cerebral malformations -> AVM/CCM
186
Q

Name some diseases caused/linked by excessive angiogenesis.

A
  • retinal disease
  • cancers
  • atherosclerosis
  • obesity
187
Q

How are blood vessels made?

A

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.

188
Q

Describe the process of angiogenesis.

A
  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
189
Q

Name 3 activators of angiogenesis.

A
  • VEGFs
  • FGFs
  • PDGFB
  • EGF
  • LPA
190
Q

Name 2 inhibtors of angiogenesis.

A
  • thrombospondin-1
  • the statins -> angiostatin, endostatin, canstatin, tumstatin
191
Q

How does hypoxia trigger angiogenesis?

A
  • 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)
192
Q

What are the 5 members of the VEGF family?

A
  • VEGF-A
  • VEGF-B
  • VEGF-C
  • VEGF-D
  • PIGF (placental GF)
193
Q

What are the receptors for the VEGF family?

A
  • 3 tryosine kinase receptors called VEGFR1, VEGFR2 and VEGFR3
  • the receptors can combine to form dimers
194
Q

What are the 2 co-receptors for VEGF?

A
  • neuropilin-1 (Nrp1)
  • neuropilin-2 (Nrp2)
195
Q

What is the major mediator of VEGF-dependent angiogenesis?

A
  • VEGFR-2 is the major mediator of VEGF-dependent angiogenesis
  • activates signalling pathways that regulate endothelial cell migration, survival and proliferation
196
Q

Describe notch signalling.

A
  • 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

197
Q

What is the mechanism of notch signalling?

A
  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
198
Q

How are tip cells selected in angiogenesis?

A
  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
199
Q

How is sporut growth guided in angiogenesis?

A
  • 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
200
Q

How are newly formed vessels stabilised and quiescencted?

A
  • 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
201
Q

Describe VE-cadherin.

A
  • constitutively expressed at junctions
  • mediates adhesion between endothelial cells
  • controls contact inhibition of cell growth
  • promotes survival of EC
202
Q

Describe the angiopoietin-Tie2 signalling pathway.

A

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

203
Q

What is angiogenic switch?

A

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
204
Q

Describe tumour blood vessels.

A
  • 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
205
Q

What is the current aim of drugs targetting angiogenesis in cancer treatment?

A
  • normalise and stabilise tumour blood vessels to reduce hypoxia and improve efficiency of drug delivery to the tumour
206
Q

Is avastin a first line cancer treatment? Explain the answer.

A

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
207
Q

What are the side effecs of avastin?

A

GI perforation

  • hypertension
  • proteinuria
  • venous thrombosis
  • haemorrhage
  • wound healing complications
208
Q

What is avastin?

A
  • an anti-VEGF humainsed MAb (mouse anitbody) -> anti-angiogenesis drug
  • also called Bevacizumab
209
Q

What are the 2 main modes of resistance to VEGF blockade?

A
  • 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
210
Q

Excluding cancer, what other disease are antiVEGF drugs used?

A
  • age-related macular degeneration -> main cause of blindness
211
Q

In what disease might a diserable treatment be the promotion of angiogenesis?

A
  • ischaemic diseases
212
Q

What are the 4 main-cancer treatment modalities?

A
  • surgery
  • chemotherapy
  • radiotherapy
  • immunotherapy

o endocrine therapy is used in the treatment of some cancer -> breast

213
Q

What are the two major branches of systemic theraphy against cancer?

A
  • cytotoxic chemotherapy -> kills cells
  • targeted therapies
214
Q

What are the 5 main branches of cytotoxic chemotherapy drugs?

A
  • alkylating agents
  • antimetabolites
  • anthracyclines
  • vinca alkaloids and taxanes
  • topoisomerase inhibitors
215
Q

What are the 2 mian branches of target therapies against cancer?

A
  • small molecule inhibitors
  • monoclonal antibodies
216
Q

What is the general target for cytotoxic chemotherapy drugs?

A
  • 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
217
Q

What is the mode of administration for cytotoxic chemotherapy?

A
  • IV or oral
218
Q

What is the mechanism of alkylating agents?

A
  • add alkyl (CNH2N+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)
219
Q

What is the major risk of alkylating agents?

A
  • can lead to secondary cancers such as leukaemia
  • benefits of this treatment outweigh the negatives
220
Q

Name some alkylating agents.

A
  • chlorambucil
  • cyclophosphamide
  • dacarbazine
  • temozolomide
221
Q

What is the mechanism of pseudo-alkylating agents?

A
  • 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)
222
Q

Name some pseudo-alkylating agents.

A
  • cisplatin
  • carboplatin
  • oxaliplatin
223
Q

What are the side effects of alkylating and pseudo-alkylating agents?

A
  • cause hair loss (not carboplatin)
  • nausea
  • vomiting
  • diarrhoea
  • immunosuppression
  • tiredness
  • nephrotoxicity
  • neurotoxicity
  • ototoxicity (toxic to the ear) (platinums)
224
Q

What is the mechanism of anti-metabolites?

A
  • 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
225
Q

Name some anti-metabolites.

A
  • methotrexate (folate)
  • 6-mercaptopurine
  • decarbazine and fludarabine (purine)
  • 5-fluorouracil
  • capecitabine
  • gemcitabine (pyrimidine)
226
Q

What are the side effects of anti-metabolites?

A
  • 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
227
Q

What is the mechanism of anthracyclines?

A
  • 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
228
Q

Name some anthracyclines.

A
  • doxorubicin
  • epirubicin
229
Q

What are the side effects of anthracyclines?

A
  • 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”)
230
Q

What is the mechanism of action of microtubule targeting drugs?

A
  • vinca alkaloids = inhibit assembly of mitotic microtubules
  • taxanes = inhibit dissembly of mitotic microtubules

o both cause dividing cells to undergo mitotic arrest

231
Q

What are the side effects of microtubule targeting drugs?

A
  • nerve damage -> peripheral neuropathy, autonomic neuropathy
  • hair loss
  • nausea
  • vomiting
  • bone marrow suppression -> neutropenia, anaemia thrombocytopenia
  • arthralgia -> pain in joints
  • allergy
232
Q

What is the mechanism of topoisomerases inhibtors?

A
  • 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
233
Q

What are the side effects of topoisomerase inhibitors?

A
  • 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
234
Q

Why are topoisomerase inhibitors often administrated with atropine?

A
  • in an attemot to minimalise the diarrhoea, abdominal cramps and sweating
235
Q

What are the mechanism of drug resistance against cytotoxic chemotherapy treatments?

A
  • 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
236
Q

What are the 10 hallmarks of the cancer cell?

A
  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
237
Q

What is the mechanism of monoclonal antibodies?

A
  • 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
238
Q

Give some examples of monoclonal antibodies used in oncology.

A
  • bevacizumab binds and neutralises VEGF -> improves survival in colorectal cancer
  • cetuximab targets EGFR -> also used in colorectal cancers
239
Q

What is the mechanism of small molecule inhibitors?

A
  • small molecule inhibitors bind to the kinase domain of the tyrosine kinase within the cytoplasm
  • block auto-phosphorylation and downstream signalling
240
Q

Give an example of a small molecule inhibitor used in cancer treatment?

A
  • GLIVEC (imatinib)
  • targets bcr-abl protein specifically -> this protein drove the over-production of WBCs in CML
241
Q

What are the mechanims of resistance against targeted therapies?

A
  • 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
242
Q

What is the mechanism of anti-sense oligonucleotides?

A
  • 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
243
Q

Why do we need programmed cell death?

A
  • 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
244
Q

What is the difference between necrosis and apoptosis?

A
  • 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
245
Q

Describe necrosis.

A
  • 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
246
Q

Describe apoptosis.

A

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

247
Q

What will neighbouring cells, to a cell undergoing apoptosis, do?

A
  • will form over the top of the dying cell to maintain the constant epithelial barrier
248
Q

What are the 4 brackets of cell death?

A
  • 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

249
Q

What are the 4 major mechanism of apoptotic cell death?

A
  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
250
Q

What are the 2 classes of caspases?

A

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
251
Q

Describe caspase maturation.

A
  • 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
252
Q

What is the main purpose of the caspase cascade?

A
  • amplification
  • divergent responses
  • regulation

o inititaor caspases cleave and activate effector caspases

253
Q

How do effector caspases execute apoptosis?

A
  • 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)
254
Q

What are the mechanisms of caspase activation?

A
  • death by design -> receptor-mediated (extrinsic) pathways
  • death by default -> mitochondrial (intrinsic) death pathway
255
Q

Describe the structure of death receptors.

A
  • all cells have death receptors on their surface consisting of:
  • extracellular cysteine-rich domain
  • single transcellular domain
  • cytoplasmic tail (with a death domain)
256
Q

What activates death receptors?

A
  • encounter secreted or transmembrane trimeric ligands (e.g. TNF-alpha or Fas) -> these are called DEATH LIGANDS
257
Q

What is the role of FADD?

A
  • 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
258
Q

What is the role of FLIP?

A
  • 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
259
Q

What is the role of adaptor proteins in receptor-mediated apoptosis?

A

o to regulate apoptosis

  • FADD = activation of cell death
  • FLIP = inhibition of cell death
260
Q

Describe the structure of adaptor proteins in receptor-mediated apoptosis.

261
Q

What is caspase-8?

A
  • an initiator caspase -> activates caspase 3 and 7
262
Q

Describe death by default mechanism.

A
  • 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
263
Q

Describe the structure of the apoptosome (wheel of death).

A
  • 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
264
Q

What is the apoptotic role of APAF-1 heptamer?

A
  • 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
265
Q

Describe the protein called Bid.

A
  • 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
266
Q

What are the pro-apoptotic members of the Bcl-2 family?

A
  • Bid
  • Bad
  • Bax
  • Bak

o move between cytosol and mitochondria

267
Q

What are the anti-apoptotic members of the Bcl-2 family?

A
  • Bcl-2
  • Bcl-xL

o localised to the mitochondrial membrane

268
Q

How do growth factors bring about cell growth and proliferation/act against apoptosis?

A
  • 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
269
Q

How does PKB/Akt induces cell survival by blocking apoptosis?

A
  • 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
270
Q

What are the steps of tumour progression?

271
Q

What is required for metastasis to occur?

A

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
272
Q

What are the 2 types of cell motility?

A
  • individual -> single cell migration
  • collective -> group of cells
273
Q

What cancer metastase by amoeboid?

A
  • lymphoma
  • leukaemia
  • SCLC
274
Q

What cancers metastase by mesenchymal (single cell/chains)?

A
  • fibrosarcoma
  • glioblastoma
  • anaplastic tumours
275
Q

What cancers metastase as clusters/cohorts?

A
  • epithelial cancers
  • melanoma
276
Q

What cancer travel as multicellular (strands/sheets)?

A
  • epithelial cancers
  • vascular tumours
277
Q

What do tumour cell metastases mimic?

A

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
278
Q

If cells are seperated/scraped apart, how will normal and cancer cell react?

A
  • 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
279
Q

What stimuli are required for a cell to move?

A
  • organogenesis and morphogenesis
  • wounding
  • growth factors/chemoattractants
  • de-differentiation (tumours)
280
Q

What changes occur in the morphology of a cell when it moves?

A
  • directionality (polarity) of movement that is essential
  • become larger in the direction that they are moving
281
Q

Name some specialised structures that are required for movement.

A
  • focal adhension
  • lamellae
  • filopodia
282
Q

How does a cell normally know when to stop moving?

A
  • contact-inhibition motility
283
Q

How do cells attached to the ECM move?

A
  • 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
284
Q

What are filopodia?

A
  • 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
285
Q

What are lamellipodia?

A
  • 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
286
Q

What is the difference between cell movement and motility?

A
  • motility = the movement of a cell in space
  • cell movement = change in cell shape which makes movement possible
287
Q

What are the 2 types of cell motility?

A

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
288
Q

What are the stages of cell motility?

A
  • similar to us rock-climbing
289
Q

How is actin involved in the movement of a cell?

A
  • 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
290
Q

How are actin filaments arranged in filapodium, stree fibres and lamellipoda?

A

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

291
Q

What are the different structures that cells can form from their actin filament?

292
Q

Describe nucleation of actin.

A
  • 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
293
Q

Describe elongation of actin.

A

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)
294
Q

Describe capping of actin.

A
  • 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
295
Q

Describe serving of actin.

A
  • 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
296
Q

Name some capping proteins.

A

+ end = Cap Z, gelsolin, fragmin/severin

  • end = tropomodulin, Arp complex
297
Q

Name some serving protein.

A
  • gelsolin
  • ADF/cofilin
  • fragmin/severin
298
Q

What 4 process are involved in creating a single actin filament?

A
  • nucleation
  • elongation
  • capping
  • serving
299
Q

Describe cross-linking and bundling of actin.

A
  • 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
300
Q

Which protein involved in the cross-linking and bundling of actin is often upregulated in tumours?

301
Q

Which protein involved in crossing-linking and bundling of actin is mutated in Duchenne muscular dystrophy?

A
  • dystrophin
302
Q

Describe branching of actin?

A
  • 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
303
Q

Describe gel-sol transition by actin filament serving.

A
  • 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
304
Q

Name some disease which are caused by dysregulation of the actin cytoskeleton?

A
  • hypertension
  • Wiskott-Aldrich Syndrome -> immunodeficiency, eczema, autoimmunity
  • Duchenne Muscular Dystrophy (muscle wasting)
  • Bullous Pemphigoid (autoimmune disease)
305
Q

Which one of these diseases is not caused by deregulation of actin cytoskeleton?

a) High blood pressure
b) Wiskott-Aldrich Syndrome – WAS (immunodeficiency, eczma, autoimmunity)
c) Duchenne Muscular Dystrophy (muscle wasting)
d) Bullous Pemphigoid (autoimmune disease)
e) Alzheimer (neurodegenerative)

306
Q

How do lamellae protude?

A
  • 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)
307
Q

How do filopdia protrude?

A
  • 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.
308
Q

What signalling mechanisms regulate the actin cytoskeleton?

A
  • 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
309
Q

What is Rho?

A
  • a subfamily of 20 small GTPases belongs to the Ras super-family
  • levels are often upregulated in cancers
310
Q

How is the actin cytoskeleton controlled by small G proteins?

A
  • 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
311
Q

What happens when 3 members of the Rho family, called Cdc42, Rac and Rho are activated in cells?

A
  • Cdc42= induces filopodia
  • Rac = huge expansion and flattening of the cell
  • Rho = indcues stress fibres
312
Q

Why are the vast majority of breast cancers treatable?

A
  • are due to oestrogen driving their growth -> therapies can be designed against this
313
Q

What is the most common breast cancer?

314
Q

Describe the development and structure of the breast?

A
  • 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

315
Q

Describe the cellular organisation of the mammary gland.

A
  • 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
316
Q

How does breast cancer progress from normal to malignant?

A

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

317
Q

What risk factors are very due to lifetime of exposure to oestrogens?

A
  • 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
318
Q

What kind of receptor is the oestrogen receptor?

A
  • nuclear receptor -> when bound to oestrogen on the nucleus of a cell it becomes a transcription factor
319
Q

What does the oestrogen induced genes drive?

A
  • cell proliferation -> can lead to cancer -> cyclin D1, C-myc and TGF-alpha are commonly affected in breast cancers
320
Q

What receptor is upregulated by oestrogen?

A
  • 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
321
Q

What paradox exist between the treatment of breast cancer for pre and post-menopausal women?

A
  • 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
322
Q

True or False. All breast cancers are oestrogen responsive to some degree.

323
Q

What is the problem with synthetic oestrogen treatment for breast cancer?

A
  • not well tolerated
  • resistance often follows remission -> patients can get metastatic disease
  • drugs must be given in high dose (and have many side effects)
324
Q

What is the primary treatment for breast cancer?

A
  • surgery -> from lumpectomy to full mastectomy
325
Q

What is the standard treatment plan for breast cancer?

A
  • 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
326
Q

What are the 3 key approaches to the endocrine therapy in breast cancer?

A
  • ovarian suppression (in pre-menopausal women)
  • blocking oestrogen production by enzymatic inhibition
  • inhibiting oestrogen responses
327
Q

Describe the steps that lead to oestrogen reaching the lungs.

328
Q

Describe ovarian ablation.

A
  • 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
329
Q

What is the major issue with ovarian ablation and which approaches of ablation cause it?

A
  • 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
330
Q

Describe the phramacological approach to ovarian ablation.

A
  • 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”

331
Q

What are the endocrine therapy lines of treatment for post-menopausal women?

A
  • aromatase inhibitors
  • anti-oestrogens
332
Q

What is the most commonly used anti-oestrogen?

333
Q

Describe tamoxifen in terms of cancer treatment.

A
  • 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
334
Q

What class of drug is tamoxifen, and why is this relevant in the treatment of cancer?

A

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
335
Q

What are the unwanted effects of tamoxifen?

A
  • increase in vasomotor symptoms
  • increased cataracts
  • increases thromboembolism
  • promotes endometrial cancer, fibroids, polyps and vaginal discharge
336
Q

What are the problems with using tamoxifen as a preventative method against breast cancer?

A
  • despite reducing overal breast cancer incidence it does increase incidence of endometrial cancer, stroke, DVT and cataracts
337
Q

Why can aromatase inhibitors be used in the treatment of breast cancer?

A
  • 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

338
Q

What is the front-line endocrine therapy for post-menopausal women?

A
  • aromatase inhibtors
339
Q

What are the 2 classes of aromatase inhibitors?

A
  • 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
340
Q

Describe progetins use in breast cancer.

A
  • 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
341
Q

What is the major probelm with breast cancer treatment?

A
  • 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
342
Q

What are the risk factors for breast cancer?

A
  • 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)
343
Q

What are the functions of the colon?

A
  • 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)
344
Q

Describe cell turnover in the colon.

A
  • 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
345
Q

What is a polyp?

A
  • a projection from a mucosal surface into a hollow vicus
346
Q

Describe hyperplastic polyps.

A
  • 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
347
Q

What is a colonic adenoma?

A
  • benign neoplasm of the mucosal epithelial cells – associated with increased cancer risk
348
Q

What are the colonic polyp types?

A
  • metaplastic/hyperplastic -> completely benign and very common
  • adenomas -> increase risk of cancer
  • juvenile
  • Peutz Jeghers
  • lipomas
  • others (essentially any circumscribed intramucosal lesions)
349
Q

How are colonic adenomas classified?

A
  • 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
350
Q

Describe tubular adenomas.

A
  • columnar cells will have some nuclear enlargement, elongation, multi-layering and loss of polarity
  • increased proliferative activity
  • reduced differentiation
  • complexity/disorganisation of architecture
351
Q

Describe villous adenomas.

A
  • 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
352
Q

What is adenomatous polyposis?

A

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.)
353
Q

What percentage of over 50s have an adenoma and what percentage of these become cancer?

A

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
354
Q

What are the 2 genetic pathways in colonic cancer?

A
  • adenoma carcinoma sequence
  • microsatellite instability
355
Q

Describe the adenoma carcinoma sequence.

A
  • 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

356
Q

Describe microsatellite instability leading to colonic cancer.

A
  • 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
357
Q

What are the 2 genetic pre-disposition to colonic carcinoma?

A
  • FAP = inactivation of APC tumour suppressor genes
  • HNPCC = microsatellite instability
358
Q

What age, sex and food culture are most patients with colonic cancer?

A
  • 50 to 80
  • equal incidence in men and women
  • western diet
359
Q

What foods increase the chances of colonic cancer?

A
  • high fat
  • low fibre
  • high red meat
  • refined carbohydrates
360
Q

Name some foods/element of food that are “anti-cancer”.

A
  • 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
361
Q

What is the classical presentation of colorectal cancer?

A

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)
362
Q

Describe the distribution of colorectal cancer?

A
  • 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%
363
Q

What types of carcinomas do you get in the colon?

A
  • adenocarcinomas -> derived from glands
  • are some sub-tupes of adenocarcinomas but these are rare -> mucinous carcinoma, signet ring cell and neuroendocrine
364
Q

How is the grading of colonic cancer distributed?

A
  • 10% well differentiated -> looks like the glands it originally come from
  • 70% moderately differentiated -> MOST CANCERS IN THE GI TRACT
  • 20% poorly differentiated
365
Q

What are the apical lymph nodes?

A
  • 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
366
Q

What is the treatment for colorectal cancer?

A
  • 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
367
Q

Describe colorectal cancer screening.

A

o high risk screening

  • previous adenoma
  • 1st 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

368
Q

What age does the NHS screening for colon cancer begin?

A
  • 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)
369
Q

A 76-year-old man presents with new onset rectal bleeding to the GP:

A. Haemorrhoids must be excluded in the first instance

B. Factor 5 Leiden abnormalities are the likely cause

C. The GP should reassure and send the patient home

D. Colorectal malignancy must be excluded in the first instance

E. Crohn’s disease must be excluded in the first instance

A
  • D
  • exclude the most serious issue first unless an obvious other causes (large piles) are present
370
Q

With respect to the aetiology of colorectal adenocarcinoma:

A. Many carcinomas are derived from adenomas

B. Adenomas are invasive tumours

C. Ulcerative colitis is the underlying cause in many cases

D. Many carcinomas are derived from hyperplastic polyps

E. Angiodysplasia is the underlying cause in many cases

371
Q

What cancer terms can be used for most cancers but not leukaemia?

A
  • 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
372
Q

What terms are used to describe the severity of leukaemias?

A
  • 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
373
Q

What are the four main categories of leukaemia classification?

A
  • acute lymphoblastic leukaemia (ALL)
  • acute myeloid leukaemia (AML)
  • chronic lymphocytic leukaemia (CLL)
  • chronic myeloid leukaemia (CML)
374
Q

What leads to leukaemia?

A
  • 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
375
Q

Name some inherited/constitutional abnormalities that can contribute to leukaemogenesis.

A
  • 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
376
Q

Name 4 identified leukaemogenic environmental factors.

A
  • irradiation
  • anti-cancer drugs are themselves leukaemogenic
  • cigarette smoking
  • chemicals -> e.g. benzene
377
Q

What is the difference beteen acute and chronic myeloid leukaemia?

A

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
378
Q

What is the difference between acute and chronic lymphoid leukaemia?

A

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

379
Q

What are some clinical characteristics of leukaemia?

A
  • 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
380
Q

What are the metaboic effects of leukaemia?

A
  • 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
381
Q

What are the clinical features of ALL?

A
  • 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)
382
Q

What are the haematological features of ALL?

A
  • 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
383
Q

What investigations are carried out if ALL is suspected?

A
  • 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
384
Q

What is immunophenotyping?

A
  • 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

385
Q

What cells express CD19?

386
Q

What cells express CD10?

A
  • is the common antigen -> expressed on B cells
387
Q

What cells express TDT?

A
  • immature blast cells
388
Q

What are the leukaemonegnic mechanisms in ALL?

A
  • 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
389
Q

What are the chromosomal sites commonly translocated in leukaemia?

A
  • 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
390
Q

What is the treament for ALL?

A
  • 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
391
Q

What are the layers of skin?

A
  • from top to bottom

o epidermis

o dermis -> fat and subcutaneous tissue as well as blood vessels and nerves

o hypodermis

  • muscle
392
Q

What cells give rise to most skin cancers?

A
  • epidermis cells
393
Q

Describe the structure of the epidermis.

A
  • 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
394
Q

Name some types of skin cancer.

A
  • 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
395
Q

Which skin cancer is associated with HIV?

A
  • Kaposi’s sarcoma
396
Q

State the main causes of skin cancer.

A
  • 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
397
Q

What is the usually presentation of a malignant melanoma?

A
  • 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
398
Q

How are suspected malignant melanomas inspected and treated?

A
  • 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
399
Q

What group of people are more likely to suffer from a malignant melanoma?

A
  • pale skinned/caucasians who spend lots of time in high UV exposed atmospheres
400
Q

What is this?

A
  • basal cell carcinoma -> usually occur on the face (this is just above the eyebrow
  • incidence has increased due to less people wearing hats
401
Q

Describe the UV spectrum and state which is the most important in causing skin cancer?

A
  • 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

402
Q

How does UVB light cause DNA mutations?

A

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
403
Q

How does UVA light cause DNA mutations?

A

o UVA light also promotes skin carcinogenesis, but to a LESSER degree than UVB

  • can cause pyrimidine dimers and free radical production
404
Q

What is xeroderma pigmentosum?

A

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
405
Q

What happens in sun burn?

A
  • 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
406
Q

What are the immunomodulatory effects of UV light?

A
  • 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
407
Q

What are Fitzpatrick phototypes?

A

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

408
Q

What are the different types of melanin?

A
  • eumelanin -> darker skinned people produce compartively more
  • phaeomelanin -> lighter skinned people produce compartively more
409
Q

What is our skin colour dependent on?

A

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
410
Q

What are the dendritic cells of the skin?

A
  • melanocytes
  • Langerhans -> are APCs
411
Q

How does melanin prevent UV-induced DNA damage?

A
  • 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

412
Q

What type of cells are malignant melanomas derived from?

A
  • melanocytes
413
Q

What are the causes of malignant melanomas

A
  • UV exposure
  • genetics play a fair role
414
Q

Name 5 different types of malignant melanomas.

A
  • superficial spreading
  • nodular
  • lentigo maligna melanoma
  • acral lentiginous
  • amelanotic
415
Q

Describe lentigo maligna.

A
  • 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

416
Q

Describe superficial spreading malignant melanomas.

A
  • 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
417
Q

What is the rule about diagnosing malignant melanomas?

A

o ABCD(E)

  • Asymmetry
  • Border irregular
  • Colour variation (dark brown-black)
  • Diameter > 0.7mm and increasing
  • Erythema (redness) or Evolution (growing)
418
Q

What does a white patch in the middle/around a superficial spreading malignant melanoma mean?

A
  • it is regressing -> immune response against it is effective
  • can mean there was a thicker melanoma in that area = worse prognosis
419
Q

Describe nodular melanomas.

A
  • vertical proliferation of malignant melanocytes (with no previous horizontal/lateral growth) -> means that there is a risk of metastasis
  • can ulcerate
420
Q

Describe nodular melanoma arising within superficial spreading malignant melanoma.

A
  • 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
421
Q

Describe acral lentiginous melanoma.

A
  • 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
422
Q

Describe amelanotic melanoma.

A
  • a melanomas that can’t make melanin because they lose the ability to do so -> results in a lesion that lacks pigment
423
Q

What is the prognosis of melanoma dependent on?

A
  • Breslow thickness -> thickness measured from the top to the bottom of the lesion
  • < 1 mm = superficial tumour
  • > 1mm = deeper tumour
424
Q

What are the important risk factors in the development of malignant melanomas?

A
  • 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)
425
Q

Describe squamous cell carcinoma of the skin.

A
  • 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
426
Q

What type of cells is squamous cell carcinoma of the skin derived from?

A
  • keratinocytes -> can therefore sometimes produce keratin
427
Q

What are keratoacanthomas?

A
  • benign lesion that looks very similar to a SCC
428
Q

What sites are the most likely to get squamous cell carcinoma skin cancers?

A
  • 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
429
Q

Describe basal cell carcinoma skin cancer.

A
  • 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
430
Q

What type of cells is basal cell carcinoma skin cancer derived from?

A
  • keratinocytes at the basal layer of the epidermis
431
Q

What are the causes of squamous cell carcinoma skin cancer?

A
  • UV exposure
  • HPV
  • immunosuppression
432
Q

What are the causes of basal cell carcinoma skin cancer?

A
  • UV exposure
  • genetics
  • immunosupression
433
Q

Describe mycosis fungoides.

A
  • 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
434
Q

Describe Kaposi’s sarcoma.

A
  • 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
435
Q

Describe epidermodusplasia veruciformis.

A
  • 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)

Y2 MCD (5 decks)

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