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principles of disease > cancer week 7 > Flashcards

cancer week 7 Flashcards

1
Q

what are the 10 hallmarks of cancer

A
  • sustaining proliferative signalling
  • evading growth suppressors
  • avoiding immune destruction
  • enabling replicative immortality
  • tumour-promoting inflammation
  • activating invasion and metastasis
  • inducing angiogenesis
  • genome instability and mutation
  • resisting cell death
  • deregulating cellular energetics
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2
Q

how does a cancer cell sustain proliferative signalling

A
  • normal cells require an external growth signal to divide
  • cancer cells bypass normal growth factor pathways leading to unregulated growth
  • occurs as a result of acquired mutations
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3
Q

how do cancer cells evade inhibitory growth signals

A
  • cancer cells ignore signals

- enabled by acquired mutations and gene silencing

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4
Q

how do cancer cells avoid immune destruction

A
  • immune system can recognise and remove cancer cells
  • however some cancer cells are able to avoid detection by not initiating an immune response
  • cancer cells hijack immune checkpoints and modulate immune response via STING (signalling molecule that is crucial in controlling transcription the body’s defence genes
  • immunotherapy uses this to its advantage
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5
Q

how to cancer cells have unlimited replicative potential

A
  • normal cells have a counting device (telomeres) that monitor and adjust the number of cell doublings
  • once the cell numbers have reached this finite number they enter senescence
  • cancer cells maintain telomere length and replication overdrive begins
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6
Q

what is tumour promoting inflammation

A
  • all tumours have inflammatory immune cells
  • inflammatory cells provide growth factors that promote angiogenesis and invasion
  • cell death by necrosis gives rise to inflammation
  • necrotic cells release bioactive regulatory factors IL-1 (apoptosis doesn’t do this), these stimulate neighbouring cells to proliferate
  • inflammatory cells can release radical oxygen species that give rise to mutations
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7
Q

how do cancer cells invade and metastasise

A
  • mutations within the genome may affect the enzymes involved in cell-cell adhesion e.g. E-cadherin
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8
Q

what is angiogenesis in cancer

A
  • creation of new blood vessels by the tumour
  • provides supply of oxygen and nutrients
  • new blood vessels are friable (tear more easily) leading to tumour cell escape and increasing possibility of metastasis
  • many drugs have been developed to target angiogenesis
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9
Q

how does genomic instability lead to cancer

A
  • alterations in DNA lead to instability
  • faulty DNA repair pathways or hereditary predisposition contribute to the development of DNA alterations (mutations)
  • single point and large chromosomal abnormalities can be found in tumour DNA
  • accumulation of mutations over a period of time explains why cancer is more frequent in the ageing population
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10
Q

how do cancer cells evade cell death

A
  • cell death is either regulated (apoptosis) or unregulated (necrosis)
  • cancer cells evade death as a result of mutations within the apoptosis pathway
  • caspases play central role in apoptosis therefore mutations in this family will allow cancer cells to pass through unchecked
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11
Q

how do cancer cells deregulate cell energetics

A
  • deregulating cell energetics is reprogramming energy metabolism
  • aerobic glycolysis is used by cancer cells to redirect energy
  • this allows cancer cells to fuel cell growth and division
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12
Q

what are oncogenes

A
  • mutated gene giving rise to tumour formation in a DOMINANT fashion (so only require one allele to possess mutation)
  • all cells have the ability to become oncogenic
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13
Q

what are somatic and germiline mutations

A

somatic mutations - most common and is acquired

germline mutations - hereditary

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14
Q

what is a tumour suppressor gene

A
  • inhibits tumour formation

- mutations can occur within tumour suppressor genes (usually recessive)

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15
Q

what is G0 in the cell cycle

A

resting phase

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16
Q

what is G1 in the cell cycle

A
  • cells grow larger and copy organelles
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17
Q

what is S phase in the cell cycle

A
  • cells make a complete copy of DNA
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18
Q

what is G2 in the cell cycle

A
  • further cell growth
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19
Q

what is M phase in the cell cycle

A

the four phases of mitosis

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20
Q

what are three theories of how cancer spreads

A
  • en route theory (spread of cancer follows blood flow)
  • seed and soil theory (molecules spreading via cell surface and providing ideal micro-environment)
  • pre-metastatic niche (theory that the primary tumour prepares the site of future metastasis by secreting factors to make the new site optimal for cancer cells)
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21
Q

what do cancer cells penetrate to move into the blood stream

A

the extracellular matrix

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22
Q

what is the extracellular matrix

A
  • complex meshwork of proteins and carbohydrates
  • major component of the ECM is collagen/proteoglycans, this gives structural integrity to the tissues
  • the ECM is directly connected to the cells it surrounds, it is the interface between the cell and other surrounding structures like blood vessels
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23
Q

what are cadherins

A
  • a type of cell adhesion molecule

- these bind cells to each other and the extracellular matrix

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24
Q

what is E-cadherin

A
  • involved in cell-cell adhesion of epithelial cells

- epithelial cancers frequently show downregulation and mutation of E- cadherin

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25
Q

what are the two mechanisms of metastasis and what are their two different patterns

A

spread of tumour cells from the primary tumour is not clonal (primary tumour is composed of cells that are sub-clonal)
2 different mechanisms: monoclonal and polyclonal
2 different patterns: linear and branched
- thus giving different mutations

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26
Q

what is epithelial mesenchymal transition (EMT)

A
  • cancer cells must acquire migratory characteristics
  • EMT is the conversion of closely connected epithelial cells becoming independent mesenchymal cells with the ability to move and evade their local environment
  • this is a reversible process and usually occurs in embryogenesis, however also occurs in cancer metastasis
  • in epitherlial cells EMT results in a loss of cell polarity leading to the destruction of cell-cell junctions, giving rise to changes in cell shape
  • there is a down regulation of e-cadherin and an up regulation of n-cadherin with secreting of specific proteases and an increase in cell protrusion giving the end result of motility
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27
Q

what are the five steps in the journey to metastasis

A
  • invasion
  • intravasation
  • transport
  • extravasation
  • colonisation
    this is followed by angiogenesis
    (not all cells within the primary tumour have the ability to metastasise)
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28
Q

what are the cell adhesion molecules

A
  • cadherins (calcium dependent transmembrane proteins
  • catenins (protein inducing gene expression)
  • cadherins interact with the cytoskeleton inside the cell via catenins
  • catenins are proteins within the cell that bind to transcription factors and induce gene expression within the nucleus
  • mutations within e-cadherin can lead to inadequate cell-cell adhesion and distortion of cell shape
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29
Q

what are integrins

A
  • they enable cells to become mobile by modifying membrane distribution allowing cells to break free from the extracellular matrix
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30
Q

what do proteases do

A
  • facilitate invasion by making the pathway through the extracellular matrix, matrix metalloproteins contribute to the loss of cell junctions
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31
Q

what happens during the invasion step of the journey to metastasis

A
  • signals from the tumour (HGF, TGF-beta) help to induce EMT in the neighbouring cells by stimulating kinase receptors (EFGR)
  • these ligand bound receptors activate pathways such as the MAPK pathway which controls the genes needed to start off EMT which is what gives the cell its migratory qualities
  • cell adhesion molecules, integrins and proteases are involved
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32
Q

what do cell adhesion molecules, integrins and proteases do during the invasion step of the journey to metastasis

A
  • down regulation or mutation of cell adhesion molecules such as e-cadherin leading to inadequate cell-cell adhesion and change of cell shape
  • intergrins allow cell to break free and become mobile
  • proteases make the path through the ECM and matrix metalloproteins contribute to the loss of cell junctions
33
Q

what happens in the intravasation step of the journey to metastasis

A
  • entry into the blood or lymphatics
  • tumour cell attaches to the stroll side of the basement membrane
  • matrix metalloproteinases and serin proteases help to degrade the basement membrane
  • tumour cell passes between the endothelial cells and off into the bloodstream (transendothelial migration)
  • for the tumour cell this is more difficult in normal tissues with strong blood vessels, however new blood vessels that are created by the tumour itself are leaky and therefore allow easy access
34
Q

what happens in the transport stage of metastasis

A
  • tumour cells in the blood stream are called circulating tumour cells (CTCs)
  • circulating tumour cells can travel as a single cell or within a group of platelets known as an emboli
  • certain cancers have favourite metastatic sites (first pass organ, this is the first organ en route e.g. the lung is first pass organ of cells coming from the breast)
35
Q

what is e-selectin

A

a calcium dependent receptor which enables attachment of the cancer cells to the endothelium surface of blood vessels and passage through the endothelium (transendothelial migration)

36
Q

what happens in the extravasation step of the journey to metastasis

A
  • exit of tumour cells from blood vessels into distant tissues
  • tumour cells become trapped in capillaries
  • reverse of intravasation, although not identical
  • degrade basement membrane of endothelial side of blood vessels and migrate into storm
  • e-selectin involved
37
Q

what happens in the colonisation step of the journey to metastasis

A
  • site of metastasis is determined by the point of extravasation but also the microenvironment
  • environment must be favourable, for the tumour to grow it must create new blood vessels (angiogenesis) for nutrients and oxygen
38
Q

what are micro-metastases

A
  • tumour cells can spread throughout the body and remain dormant for years as micro-metastases, this may be due to a period of time before angiogenesis or they are being kept under control by the immune system
39
Q

what is angiogenesis

A

the formation of new blood vessels

- the angiogenic switch is dependent on the balance between pro-angiogenic factors and anti-angiogenic factors

40
Q

what are some pro-angiogenic factors

A 
VEGF
fibroblast growth factor 
hepatocyte growth factor 
epidermal growth factor 
platelet derived growth factor
41
Q

what are some anti-angiogenic factors

A 
angiostatin
endostatin
prolactin
protein 53 (p53)
thrombospondin 1 & 2
42
Q

what is VEGF

A
  • angiogenic inducer
  • vascular endothelial growth factor
  • VEGF family: A-D and placental growth factor
  • they transmit their signals via three VEGF receptors
  • VEGFR (VEGF receptors) must be phosphorylated to become activated
  • tumour cells can also stimulate nearby cells to produce VEGF and in turn promote angiogenesis
  • usually VEGF leads to gene expression
  • VEGF induced endothelial cell proliferation but it also increases permeability and leakage
43
Q

what is concomitant resistance

A
  • occasionally when a tumour is removed by surgery or radiation there can be growth metastasis that was previously dormant, this is known as concomitant resistance
  • the theory is that certain tumours fast produce pro-angiogenic factors and they all produce anti-angiogenic factors which controls the growth of distant metastasis
  • when the primary tumour is resected the inhibitors are also removed and the metastasis are switched on
  • surgery also encourages growth factors in the healing phase and therefore increases the risk of metastasis becoming activated
44
Q

what is plasminogen cleaved to form

A

cleaved to form angiostatin which is a angiogenic inhibitor

45
Q

what does endostatin do

A
  • it is an angiogenic inhibitor which block the MAPK pathway thus inhibiting gene expression
46
Q

what is the angiogenic switch controlled by

A
  • angiogenic switch controlled by hypoxia
  • tumours create a hypoxic environment activating HIF1 and beta sub-unit, triggering VEGF which is an angiogenic inducer
  • many drugs have been developed to inhibit angiogenesis e.g. TKI afatanib
47
Q

what is the aim of chemotherapy

A
  • target DNA, RNA and proteins
  • aim is to force cells into apoptosis
  • it is non-specific to cancer cells, all rapidly dividing cells are affected
48
Q

what is the delivery of chemotherapy like

A
  • IV and oral preparations
  • chemotherapy is administered in cycles because it is aimed at damaging cancer cells when they’re at their most vulnerable state while still allowing normal cells to recover, this is dependent on the pharmacokinetics such as half-life and the excretion of the drug involved
  • combination chemotherapy increases efficacy and reduces risk of resistance
49
Q

what are the three different stages you can give chemotherapy at

A

neoadjuvant - before surgery, aim to reduce cancer signs
adjuvant - reduce risk of cancer returning
disease control/palliative - aim is to control disease for as long as possible

50
Q

what are the three main types of chemotherapy

A
  • alkylating agents and platinum drugs
  • anti-metabolites
  • organic drugs
51
Q

how do alkylating agents and platinum drugs (type of chemotherapy work)

A
  • form DNA adducts blocking DNA replication
  • DNA adduct is segment of DNA bound to a cancer causing chemical
  • these drugs work in all phases of the cell cycle
52
Q

how do anti-metabolites work (type of chemotherapy)

A
  • structurally mimic essential molecules required for cell division
  • work as S phase of cell cycle
53
Q

what are some types of organic drugs in chemotherapy

A
  • vinca alkaloids
  • taxanes
  • anthracyclines
54
Q

at what stage of the cell cycle do alkylating agents and platinum drugs (type of chemotherapy) work

A

all phases of the cell cycle

55
Q

at what phase of the cell cycle do antimetabolites (type of chemotherapy work)

A
  • s phase of cell cycle
56
Q

how do vinca alkaloids (type of organic chemotherapy) work

A
  • bind to tubular and prevent microtubule assembly (this is essential for metaphase and mitosis)
57
Q

how do taxanes (type of organic chemotherapy) work

A
  • binds to beta tubular subunit inhibiting depolymerisation and disrupting mitotic spindle
  • essentially freeze mitotic spindle at that stage so it cannot progress
58
Q

how do anthracyclines (type of organic chemotherapy) work

A
  • microbial antibiotic targets topoisomerase II
  • anthracyclines inhibit topoisomerase II which is an enzyme that releases torsional stress (supercoiling of DNA) during the DNA replication
59
Q

what is the main side effect of chemotherapy

A
  • nausea and vomiting
  • many patients are given anti-emetic drugs along with chemotherapy to inhibit pathways such as 5-HT3 and NK-1 receptor pathways
  • anti-emetic drugs such as ondansetron and aprepitant
60
Q

what are some personalised systemic therapies for cancer

A
  • hormonal therapies (anti-oestrogen, aromatase inhibitors)
  • targeted therapies (EGFR, VEGF, CDK 4/6)
  • immunotherapy (PD-1, PD-L1, CTLA-4)
61
Q

what hormone is related to breast cancer

A
  • oestrogen (estradiol/esterone) play a major role
  • oestrogens promote cell proliferation within the breast tissue (higher rate of cell division=more chances for mutations)
  • prolonged exposure to oestrogen increases risk (e.g. contraceptive pill or HRT)
62
Q

what are some breast cancer hormonal therapies

A
  • anti-oestrogen = tamoxifen, this bings to the oestrogen receptor
  • aromatase inhibitors = letrozole, block conversion of androgens to oestrogen
63
Q

how does EGFR (EGF receptor) work and what does it do

A
  • EGF and its tyrosine kinase receptors are how a signal from outside a cell can be transmitted to inside the cell and stimulate proliferation
  • EGF binds to tyrosine kinase receptor on membrane (EGFR) and when this is phosphorylated leas to the activation of intracellular transducers including the RAS pathway and the MAPK pathway is activated resulting in transcription, giving gene expression and growth
64
Q

what is EGF receptor inhibitor and what does it do

A
  • target therapy for cancer
  • tyrosine kinase inhibitors
  • developed to target tumours which express the EGF receptor and block it
65
Q

what type of cancers express the EGF receptor

A

NSCLC = 20%
breast (HER2) = 2.3%
colorectal 3%

66
Q

what tyrosine kinase inhibitor (EGFR inhibitor) drugs are there for cancer

A
  • development is in its third generation
  • 1st generation = gefitinib and erlotinib
  • 2nd generation = afatinib
  • 3rd generation = osimertinib (treatment in EGFR mutation positive metastatic NSCLC who received prior TKI treatment
  • in first generation binding was reversible but in second and third generation it is irreversible
67
Q

what are the side effects of EGF receptor inhibitor targeted therapy for cancer

A
  • side effects are diarrhoea, dry skin, rash, hypertension, liver dysfunction
68
Q

what are CDK 4/6 inhibitors used for

A
  • in cancer treatments used to block the progression of cells through the cell cycle
  • they are a target cancer therapy
  • cyclin dependent kinase inhibitors
  • inhibitors such as pablociclib are responsible for blocking the pathway in metastatic breast cancer
69
Q

what does cyclin D, CDK4/6 and cyclin E do

A
  • cyclin and CDK control the passage of cells through each stage of the cell cycle
  • cyclin D along with CDK 4/6 pushes cells out of G0 to G1
  • cyclin D regulates cyclin E and pushes the cells from G1 to S phase
70
Q

how do the immune system checkpoints work

A
  • immune checkpoints ensure that self tolerance is maintained
  • immune checkpoints are activated by receptor ligand binding (PD-1 to PD-L1) and (CTLA-4 to B7), this slows down T cell activity
71
Q

what do immune checkpoint inhibitors (immunotherapy do)

A

removes the brakes on the immune system allowing increased T cell activity

72
Q

what is pembrolizumab

A
  • immunotherapy
  • it is an IgG4 monoclonal antibody (brand name is keytruda)
  • it targets the PD-1 immune checkpoint and blocks it binding to PD-L1 and PD-L2 ligands in the tumour and as a result the T cell is not turned off to cancer
73
Q

when is immunotherapy used in Scotland

A
  • NSCLC = 1st line metastatic setting with PDL1 over 50%, with no EGFR/ALK mutation, use pembrolizumab
  • NSCLC = 2nd line metastatic setting with PDL1 over 1% who received prior chemotherapy, use atezolizumab
  • melanoma = adjuvant stage 3 resected setting, use nivolumab
  • melanoma = metastatic unresectable, dual immunotherapy, use ipilimumab and nivolumab
74
Q

what are the side effects of immunotherapy

A
  • every itis!

- most common colonitis

75
Q

what are some non-specific immune therapies in cancer

A
  • innate = macrophages/NK cells

- programmed cell death pathway (PD-1) = uses immune system to attack ‘foreign’ cancer cells

76
Q

what are some specific immune therapies in cancer

A
  • monoclonal antibodies

- chimeric antigen receptor (CAR) T cells

77
Q

how do monoclonal antibodies work in immune therapy

A
  • not confined to cancer
    cancer
  • colorectal cancer = cetuximab
  • breast = trastuzumab
  • non-hodgins lymphoma = rituximab
  • so basically what you’ve done is develop your target in mice and then you’ve humanised the antibody so that your body recognises that as one of your own antibodies but it is actually a synthetic antibody
    (also used in inflammatory disease such as ulcerative colitis and rheumatoid arthritis)
78
Q

what is CAR T-cell therapy

A
  • take the patient’s own T cells and fuse them with synthetic T cell receptors that you have created that are targeting something uniquely on the surface of the cancer, then put T cells back in the body and they proliferate and attack the cancer

principles of disease (19 decks)

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