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1
Q

Describe EGFR activation of RAS

L1

A

EGF ligand binds
receptors dimerise
phosphorylation of intracellular tyrosine on the receptor.
Grb2 and SOS bind and then activate Ras (via swapping the GDP for GTP)

Ras has an intrinsic GTPase that normally cleaves the phosphate to turn itself off.

Oncogenic Ras loses this function

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2
Q

What can Ras activate?

L1

A

Ras can:
Stimulate protein synthesis and transcription (Via Raf MEK Erk1)

Stumlate cell growth, stimulate cell proliferation, and Inhibit apoptosis (Via PI3K Akt )

can even stimulate cell movement.

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3
Q

Causes of increased EGFR (or any growth factor) activity in cancers

L1

A

Autocrine activity

Mutations in receptor causing ligand independent firing

Overexpression (amplification)

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4
Q

What are exceptional responders?

L1

A

group of patients who respond well to treatments

eg: asian female non smokers nonsmalll cell lung cancer (with activating point mutation in cytoplasmic tail of EGFR) responded to Gefitinib/Erlotinib

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5
Q

Use of Cetuximab

L1

A

Standard of care for EGFR positive Colorectal cancer that does not have a Ras mutation.
(sequence ras in all colorectal tumours and if mutated then dont give Cetuximab)

Cetuximab (blocking EGFR) is really effective in someone with wildtype Ras.

No benefit in colon cancer with Ras mutation downstream from receptor.

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6
Q

Causes of loss of antigrowth (anti-replication)

L1

A

Checkpoints in cell cycle that block progression if Genome is damaged.

Rb controls entry from G1 into S phase.

When hypo phosphorylated it puts a break on cell replication.

Rb is key in whether cells divide.

Rb is abnormal in 80% of cancers.

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7
Q

describe the control of entry into S phase from G1

L1

A

cyclin D:CDK4 phosphorylate protein Rb

When hypo phosphorylated it puts a break on cell replication.

breaks come off when it is phophorylated

E2F is released, leading to entry into S phase

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8
Q

What drugs can inhibit cell replication? (inhibit insensitivity to antigrowth)

L1

A

CDK4/6 inhibitors block cell cycle progression
(eg Palbociclib)

they block progress from G1 to S phase

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9
Q

Examples of angiogenisis ACTIVATORS

L1

A

VEGF

bFGF

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10
Q

examples of angiogenesis inhibitors

L1

A

Thrombospondin - 1

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11
Q

why do cancers bleed a lot?

L1

A

the blood vessels grow too quickly and in a disorganised way are poorly supported and fragile

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12
Q

describe anti angiogenesis therapies

L1

A

Two ways:
Anti-VEGF monoclonal antibodies (Eg: bevacizumab -best known and commonly used)

Small molecules that inhibit VEGF receptor signaling (eg: Cedranib)

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13
Q

Describe limitations of angiogenesis inhibitors in cancer

L1

A

Don’t have a permanent effect once the drug is stopped eg after a year or two of treatment

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14
Q

What do telomeres do?

L1

A

they protect the ends of chromosomes from being treated like broken DNA

Act as a molecular clock
once they shorten a certain amount the cells undergo sensecence.

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15
Q

What is telomerase

L1

A

It is a reverse transcriptase that extends telomeres using RNA as a template.

Immortalises the cancer cells as they dont know when to stop

gives them similar ability as stem cells and embryonic cells

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16
Q

mechanisms leading to apoptosis

L1

A

Extrinsic pathway

Exectional Caspases (3, 6, 7) cleave cellular proteins and cell dies.

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17
Q

Describe the extrinsic pathway of cell death

L1

A 
Responds to external cell signals.
Death ligands (eg: FasL or TNF) activate caspase 8

Activated caspase 8 then activates Exectional Caspases (3, 6, 7) cleave cellular proteins and cell dies.

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18
Q

Describe the intrinsic pathway

L1

A

DNA damage and p53 activation, drugs, cell cycle abnormalities all influence the release of ctochrome - C from the mitochondria.

cytochrome-C then forms an apoptosome and activates Caspase-9

Caspase 9 then activates Exectional Caspases (3, 6, 7) cleave cellular proteins and cell dies.

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19
Q

What is Bid? (in apoptosis signaling)

L1

A

links activation of the extrinsic pathway(eg FasL) to intrinsic pathway (activating mitochondria)

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20
Q

What does Bcl2 do

(and a drug that inhibits this)

L1

A

pro survival (anti-apoptotic)

inhibits/regulates release of cytochrome c from mitochindria

Venetoclax - small molecule inhibitor, blocking Bcl2

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21
Q

(what does PTEN do)

L1

A

it is a tumour suppressor that inhibits AKT.
This results in more Bad (proapoptotic) that stimulates cytochrome- C release.

(as AKT inhibits Bad)

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22
Q

what are the 3 phases leading to avoiding immune destruction

L1 RM

A

Elimination, Equilibrium, Escape.

Eliminate - recognises cancer and destroys it

Equilibrium - cancer learns hw to bypass the immune system or the immune system “forgets” that the cancer is foreign.

Escape - Stops killing the cancer, can grow unchecked.

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23
Q

What is the immunoediting hypothesis in cancer development?

L1 RM

A

basically that we all develop cancer all the time but the immune system gets rid of almost all of them.

many mutations seen in apparently normal skin, but the cancer is actually very rare as the bodies immune system is mopping it up
(Martincorena et al, 2015)

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24
Q

how can cancer cells inhibit T cells?

and name a treatment targeting this

L1 RM

A

Have abnormalities in PD-1 and CTLA 4 (costimulation along with MHC) signaling to T cells

Nivolumab (in melanoma) - binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response

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25
Q

What is aerobic glycolysis?

why is this useful to doctors?

L1 RM

A

cancer cells preferentially go through the pyruvate -> lactate metabolism even with O2 normal present

PET scan can monitor radio-labelled glucose and watch where it is preferentially taken up

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26
Q

Why might asparin be useful in preventing/treating cancer?

L1 RM

A

because it reduces inflammation.

Recently been shown to reduce risk of colorectal cancer.
Flossman, 2007

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27
Q

what are the advantages of an unstable genome

L1 rm

A

it allows the cancer to adapt and evolve via new mutations adn adaptive resistance to chemo

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28
Q

How can genome instability be targeted?

L1 RM

A

PARP inhibitors are good at treating cancers with genomic instability. reasons unknown.

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29
Q

what cells make sex steroids?

L2 RM

A 
Androgen:
m- leydig cells in testis
f- theca cells in ovary
(+ adrenals)
Stimulated by LH

Oestrogen:
f - granulosa cells in ovary
(+ adipose tissue)
Stimulated by FSH

Progesterone:
Corpus leuteum

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30
Q

Why do females with PCOS have a higher risk of ovarian cancer

L2 RM

A

They fail to ovulate.
multiple large arrested follicles carry on producing oestrogens but dont mature to ovulate and therefore dont produce progesterone.
Progesterone is needed for differentiation (secretary phase) of endometrium development so you can go into next period

Oestrogen stimulates proliferation of the endometrium and therefore this continuous and leads to hyperplasia

leads to an increased disposition to endometrial cancer

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31
Q

Differentiate between different types and sources of stem cells

L3 RM

A

potency describes the differentiation options available.

Totipotent cells have the capacity to make an entire organism (cant self renew)
eg: a zygote (fertilised egg)

Pluripotent stem cells. Able to form any cell in the body, just not the whole organism as they need interference.
eg: embryonic stem cell.

Multipotent Stem cells. Can form multiple cell types, but all beloning to the same tissue type/lineage. Also the same as adult stem cells and can be used directly in regenerative medicine.
eg: haematopoietic stem cell

(Mesenchymal stem cells)
not actually stem cells,
stromal cells with fibroblast like appearance.
can generate bone cartilage and adipocytes.
Problem is its not just one bucket of stomal multipotent cells as they are all tissue specific.

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32
Q

Illustrate the different properties and homing characteristics of stem cells

L3 RM

A

Adult stem cells:
have a niche dependant self renewal capacity. and only multipotent

Advantages: ready to use and could be autologous(skin grafts)
Dissadvantages: limited expansion out of niche, and restricted potency

Pluripotent stem cells:
Unlimited self renewal. Can generate any cell in the body

Advantages: unlimited expansion, can generate any cell type
Challenges: making them differentiate to specific cell type needed.
Making them integrate and survive. timing(differentiation) needs to be just right
Hurdles: Immune rejection, tumourigenesis.

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33
Q

What are the important properties of stem cells?

L3 RM

A

1) They are relatively unspecified cells that can Differentiate to form specialised cells.
2) they have the ability of Self-Renewal. can divide to make daughter cells that are the same as the mother

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34
Q

define Regenerative Medicine

L3 RM

A

Repairing functionally compromised cells, tissues, or organs, by

  • Biological substitutes
  • Or stimulation of endogenous processes
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35
Q

What are the different types of adult stem cells? and where do they come from?

L3 RM

A

Haematopoietic stem cells from bone marrow. (found close to oesteoblasts and close to capillaries.

Skin stem cells, found in hair follicle bulge region or in the basal layer of the skin.

Intestine stem cells, found in the bottom of the crypts

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36
Q

What are the different types of Pluripotent stem cells? and where do they come from?

L3 RM

A

Pluripotent stem cells initially from preimplantation embryos
However immune rejection of these is an issue and also ethics.

New method:
Can force any cell to become a pluripotent stem cell
Induced Pluripotent Stem Cells
(iPSCs)

This is done by giving the somatic cellls Yamanaka factors. Yamanaka et al 2006.

Problems? cell culture can increase genome instability and they can cause cancer

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37
Q

RM. Define the process of cell ageing and senescence

L5

A

Cellular senescence is the IRREVERSABLE phenomenon by which normal diploid cells cease to divide over time

(hayflick, 1965)

  • Found that cells have a limited proliferative potential and stop dividing eventually (70 generations).
  • Senescenced cells are still metabolically active, just cant divide.
  • Most tumours overcome this somehow and are immortal.

Immortalisation requires two crisis to be overcome in human cells:

  • P53 and Rb pathway inducing sensecense
  • Telomere shortening

Senescenced cells:

  • Cannot be induced into the cell cycle by growth factors.
  • Accumulation of negative cell cycle regulators eg. p16, ARF, p53 and p21
  • are flat and bigger
  • have high β-galactosidase activity (useful to identify them)
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38
Q

RM. Understand the molecular processes that underlie cell ageing. (and senescence)

L5

A

1) Telomeres get shorter and eventually signal senescence.
- due to copying mechanism of DNA some primers on ends of telomeres are lost every time.

can be overcome by
- telomerase activity in stem cells or in cancer cells.

2)Oncogene expression can also trigger senescence.
EGF can activate PI3K pathway (important in survival and proliferation)

3) Oxidative stress, DNA damage, Irradiation and Toxins can all stimulate senescence and are useful in cancer treatments.

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39
Q

RM. Put the ageing process in the context of cancer treatment strategies

L5

A

After chemotherapy and radiotherapy most common mechanism of cell termination is senescence, not cell death..
Useful to monitor efficacy of treatments.

Oxidative stress, DNA damage, Irradiation and Toxins can all stimulate senescence and are useful in cancer treatments.

Chemotheraputic drugs and radiotherapy often us this.

FOXM1 overexpression can cause resistence to senescence and hence resistance to chemo.

Also experiments have shown that if Small interfering RNA is used to knock down FOXM1 then cells go into senescence

“FOXM1 Depletion Resensitizes Resistant breast cancer cells to DNA Damaging Agents”
(Kwok et al, 2010)

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40
Q

What does PTEN do?

L5

A

PTEN is an important tumour suppressor that antagonises the activity of PI3K and hence reduces the ammount of Akt (also called PKB) produced.

AKT then inhibits FOXO transcription factors which normally transcribe genes for apoptosis and growth arrest

FOXO in turn inhibit FOXM1 which is thought to be one of the earliest oncogenes activated and is v important in overcoming senescence

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41
Q

What are the effects of FOXM1

L5

A
  • it inhibits cellular senescence
  • hence abnormally high levels can cause resistance to chemo.
  • probably due to FOXM1 increasing speed that damaged DNA is repaired.

also

  • it stimulates angiogenesis
  • it leads to cell migration and invasion.
  • it causes cell cycle progression, growth, and survival

Also experiments have shown that if Small interfering RNA is used to knock down FOXM1 then cells go into senescence

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42
Q

LO: Discuss the differences and similarities between the main types of cell surface receptor receptor types

L8 - Apparently a big hint so learn well

A

1) Enzyme linked receptors:
Important growth factor receptors and cell survival

Single trans-membrane proteins
Ligand activated
Dimerise (identical receptors)
Intracellular domain Tyrosine kinase transphosphorylates opposite dimer.

Regulated by phosphotases that take the phosphates off
(Phosphorylation causes ACTIVATION)

2) Cytokine receptors:
Important in immunity and inflammation by regulating cell survival proliferation and differentiation.
(2 types depending on the ligands they can bind)
Ligands include IL3, TNFa, IFN and TF.

Single trans-membrane proteins
Must form dimers/trimers of DIFFERENT polypeptide chains to work
NO built in tyrosine Kinase
they assosiate with a kinase (JAKs) instead
JAKs activate STATs that then dimerise and act as transcription factors.

Can also switch on MAPK pathway in similar manner to TKRs.

Regulated by phosphotases that take the phosphates off
(Phosphorylation causes ACTIVATION)

3) G protein coupled receptor
SINGLE polypeptide chain that passes through the membrane 7 TIMES.
Can form both homo and hetro dimers
MOST DIVERSE set of receptors and ligands (eg: from light or ions to amino acids or proteins)
Hetrotrimeric G protein with alpha beta and gamma subunits

Phosphorylation causes INACTIVATION

COMMON FOR ALL
Also, after signaling, the receptors are internalised into an “early endosome” and then can either be quickly recycled back to the surface or degraded by lysosomes.
In cancer the degradation process can be blocked, leading to more recycled back to the surface

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43
Q

What are the two important steps in Receptor Tyrosine Kinase activation

L8

A

1) They must dimerise

2) Transphosphorylation each receptor phosphorylates the other one in the dimer.

44
Q

Describe the RTK clasical signaling pathway (GF/RTK/Ras/MAPK)

L8

A

GF binds to extracellular domain of RTK

RTK dimerise and phosphorylate each other.

Grb2 then binds
Grb2 then forms complex with SOS.
This complex then activates Gprotein called RAS

(RAS kicks off GDP and binds GTP to make activated RAS)

Activated RAS activates the MAP Kinase cascade

Ras activates Raf which activates Mek which activates Erk which activates various transcription factors

HOWEVER
most growth factors will activate more than just the Ras pathway.

eg; EGF/EGFR activates
MAPK cascade
PI3-AKT pathway (cell survival)
and many more

Regulated by phosphotases that take the phosphates off

Mutations in RAS can mean that it is constanly bound to GTP
Or mutations causing downregulation of protein that should gonvert the GTP to GDP.

45
Q

Describe the Cytokine receptor classical signalling pathway. (JAK/STAT)

L8

A

ligand binds and receptors dimerise/trimerise
JAKs cross-phosphorylate eachother.
Activated JAKs phosphorylate tyrosines on receptors
STATs then dock on to the phosphorylated residues on the receptors.
STATs then dimerise themselves and dissociate from the receptor
This new dimer migrates to the nucleus, bind to DNA and switch on transcription.

Cytokine receptors can also activate the RAS(MAPK) pathway.

REGULATED by

  • phosphotases that take the phosphates off
  • SOCS inhibit STATs signaling by competing for binding to JAK
46
Q

describe G protein coupled receptors

L8

A

G protein coupled receptor
SINGLE polypeptide chain that passes through the membrane 7 TIMES.
MOST DIVERSE set of receptors and ligands (eg: from light or ions to amino acids or proteins)
Can form both homodimers for ampligication and hetrodimers with altered ligand binding and response

Coupled to hetrotrimeric G protein (with alpha beta and gamma subunits)

G- proteins are inactive when they are GDP bound but become active when when the ligand binds to the receptor and the GDP is swapped for GTP.
the Beta and gamma subunits then dissasociate from the alpha subunit

this then can cause either:
stimulates cAMP
inhibits cAMP
calcium signaling
Depending on the type of alpha subunit
  • Can activate many different effectors throughout the cell
  • Can activate RTKs

play a central role in almost all systems

very common drug target (over 40% of drugs target them)

REGULATION:
Can be desensitized by prolonged exposure to stimulus.

Phosphorylation causes INACTIVATION

two types:
1-Second messenger kinases that are switched on by own pathway. (phosphorylate at single site.) eg cAMP activates protein Kinase A
2-GRKs phosphorylate activated receptors at multiple sites, this allows beta-arrestin to bind that stops signaling

Also, after signaling, the receptors are internalised into an “early endosome” and then can either be quickly recycled back to the surface or degraded by lysosomes

47
Q

LO: Compare and contrast different DNA alterations

L7

A

Gene mutations:

  • Deletion (of a base pair) that can cause a frameshift as a DNA code is read in triplets that code for amino acids
  • Insertions (similar effect)

-Substitution (wrong base pairs matched together)

Chromosome mutations:
-Tanslocations (chromosomes exchange bits) can cause some genes to be duplicated and thus increase expression.
Also can cause frameshifts
-duplications. (where extra copies of genes are generated)
-deletion (when some genes break off and go missing)
-Inversion (where some chromosome segments get reversed)
-Translocations (when a fragment from one chromosome breaks off and attaches to another chromosome.

DNA is especially vunerable during interphase when it is replicating

Some chemicals (carcinogens) have a high affinity for DNA and can result in ADDUCTS or MODIFICATIONS of sugar phosphate backbone or even cause strand breaks
This all interferes with the way that the dna can be transcribed
48
Q

LO: List different carcinogens and cancers in which they are known to play key roles

L7

A

Carcinogens can be inert pro-mutagens that are altered to their active form in the body

DIET
Red meat
Burnt/charred food - bowel cancer

VIRUSES:

  • Hepatitis C Virus (HCV) can lead to LIVER CANCER
  • HPV (human papilloma virus) can lead to cancer in moist membranes eg: cervix, anal, mouth and throat. (sexually transmitted)

Radiation: on flights

X-rays - all types

CHIMNEY sweepers - Scrotal cancer

Smoking: - Lung, oral…

Chemical compounds (environmental chemicals or endogenous ones)

Fine/radioactive mining powders: -Lung cancer

UV radiation: Sunbathing (burning): - skin

Infections
Chronic Inflammation
eg: IL-6 activate JAKs that activate transcription leading to growth promotion

49
Q

LO: Describe basic principles of cancer formation and progression.

L7

A

FORMATION:

  • Most tumours are monoclonal
  • Then EVOLUTIONARY pressure causing the cell clones to get successive multiple alterations.
  • these can occour in many different combinations leading to large ammounts of heterogeneity. This is why when we use drugs there will always be cells resistant because additional mutations (or even lack of the mutation the drug targets)

PROGRESSION
(SUMMARY OF HALLMARKS)
-Cancer cells dont care about contact inhibition

  • Oncogenes become activated (eg making GFs)
  • inactivation of tumour suppressors.
  • they alter their metabolism pathways
  • stimulate angiogenesis
  • Telomerase activation
  • resisting cell death.
  • evade the immune system
    (however, not all tumours are immunogenic or easily recognisable, new treatments to try to make these cancers visable eg CAR -T cells)

-eventually escapes/invades/metastasises which is what is v dangerous

Inflamation also plays a role as proinflammatory cytokines have growth promoting properties
eg: IL-6 activate JAKs that activate transcription

50
Q

Describe a typical progression of mutations in colon cancer

L7

A

Loss of APC tumour suppressor gene leading to small growth (polyp)

Activation of K-Ras oncogene leading to a class II adenomea (benign)

Loss of DCC tumour suppressor gene leading to class III adenoma (benign)

Loss of p53 tumour suppressor leading to a malignant(invasive) carcinoma developing.

51
Q

How do viruses lead to cancer?

L7

A

Slowly transforming viruses: viruse genome is inserted near a proto-oncogene and the virus promoter lead to overexpression of that proto-onc

(Acutely transforming: carry an oncogene that is immediately activated once inside the cell)

52
Q

Cancer Risk factors

L9

A

Age
Genetics

Smoking
obesity
Viruses
inactivity (independent of obesity)
Diet
Alcohol
infections
UV light
40% of cancers could be prevented by behaviour changes.(however these are very difficult to sustain) 
Genetics
Individual mutations (identified via Genome wide association studies) can have a very small effect on the relative risk on their own.

A large amount of these individual “snips” can increase the absolute risk of getting Breast/ovarian cancer.
The change in risk is exaggerated with age

53
Q

what are the hormonal cancers?

A

Brest, ovarian, endometrial cancers. Have reproductive risk factors (ie age of of menarche/menopause, age when having children, no of children)

54
Q

Epigenetics mechanisms altering transcription

L9

A

All about how the DNA is packaged.
(DNA is wrapped around histone octomers to form nucleosomes which then are packaged to form chromatin)
Epigenetic patterns determine how the DNA is open or closed, altering their transctiption.

Different types:

DNA METHYLATION

(“DNA methyltransferases attach a methyl groups to cytosine residues in cytosine/guanine(CpG) sites of a CpG island - an area with many CpG dinucleotide repeats. CpG islands are often found in promoter regions of genes and methylation in these sites typically leads to less gene expression (due to the methyl-group physically obstructing transcription factors binding)”)

  • Addition of a methyl group to a cytosine in a CpG site.
  • most genes (about 60%) have CpG island
    promoters, typically unmethylated
  • increased DNA methylation silences genes in cancer, including important tumour suppressors.
  • Studies have shown that if you knock out DNA methyl transferases then genes come back on (proof of principle)
  • DNA methylation is copied in Mitosis
  • contraversial if any are copied in meiosis

-DNA methylation is associated with age (age acceleration is when someones predicted age is higher then actual)
Age acceleration is associated with mortality.
Also associated with BMI, Stress, air pollution…

(effect of DNA methylation varies depending on location of CpG site. Methylation of CpG sites in CpG islands leads to reduced gene transcription whereas methylated non-island CpG increases transcription)

HISTONE MODIFICATION

Histones have N-terminal tails that protrude outwards and can be modified in many ways (phosphorylation, methylation, acetylation…)
Different combinations of modifications can dictate whether the dna is open or not.
eg: Acetyl groups repel eachother, opening the DNA up.
Methyl groups attract eachother, condensing the dna

  • “writers” add the methyl/acetyl groups, “erasers” take them away. readers interact with them as effector proteins.

(These tails interact with tails from adjacent nucleosomes, each of these modifications leads to a change in the three dimensional shape of the chromatin structure.
Gene expression is dependant on the three-dimensional availability of the DNA so these subtle changes can actually result in changes in gene expression)

DNA METHYLATION CAN EFFECT HISTONE MODIFICATIONS.

eg attachment of histone deacetylases (HDAC) to the methylated DNA remove the acetyl groups from the histone tails.
Once the acetyl group is removed from the histone tails, then Histone Methyl Transferases (HMT) attaches to the methyl group and causes histone tail methylation

THERAPIES:
Good for haematological tumours but less effective for Epithelial ones
Also quite toxic as they are non specific, effecting whole genome. (no speceficity)

DNA methyltransferase Inhibitors have been approved for some high risk leukemias however are quite cytotoxic

Histone Deacetylase inhibitors for advanced T cell lymphoma

Future may involve targeting specific sites by attaching the DNA methyl Transferases or Demethylating agents to CRISPR/cas9, altering the specific epigenome
Current research in labs seems to be working.

55
Q

what are the hormonal cancers?

L10

A

Brest, ovarian, endometrial cancers. Have reproductive risk factors (ie age of of menarche/menopause, age when having children, no of children)

56
Q

summarise breast cancer risk, incidence and mortality

L10

A

Key risk factors:
Age, BMI, (Hormonal factors ie Age of:) Menarche, first birth, menopause, Genetic factors (eg: BRCA1/2, p53), large amounts of associated SNPs, family history, Breast density.
Epigenetic patterns

ACCORDING TO Cancer research UK
Risk= 1/8f or 1/800m

Incidence is increasing because:
-Increase in diagnoses
-Increase in population distribution of risk
factors( eg increase in obesity and having children later)

Mortality is decreasing as:

  • Increased diagnosis of treatable cancer
  • Better targeted treatments (Tamoxifen)
  • Mammographic Screening
57
Q

how does SMOKING cause Epigenetic Variation and Cancer Risk

L10

A

CAUSES
can different exposures cause epigenetic changes?
CONSEQUENCES
can these changes be associated with cancer risk?
Did Epigenome Wide Association Studies

Causes:
Smoking- found methylation patterns associated with smoking. (Mostly hypomethylation)
Eg: smokers have less methylation of AHRR promoter hence increased transcription.
Can take up to 40 years before methylation markers come down to normal average.
hence is a good biomarker measuring longterm exposure
(can even use epigenome markers to predict if someone has been a smoker)
These markers mediates some of the lung cancer risk (about 30%) but not all of it
- Also can be detected in breast epithelial cells.

58
Q

how does ALCOHOL cause Epigenetic Variation and Cancer Risk

L10

A

Alcohol inhibits the pathway (folate pathway) that is needed to make the things(SAMs) needed for DNA methylation.

heavy drinking is associated with oesophageal, liver, gallbladder cancers

BUT ALSO with breast cancers, possibly through these epigenetic changes
In breast tissue DNA methylation goes down as alcohol intake increases.

59
Q

LO: outline the process of apoptosis

L11

A

PROCESS:

Initiator caspases
8 - has Death Effector Domain (DED)
9 - has Caspase Recruiting Domain CARD)

Death-receptor(eg: Fas)/extrinsic pathway.
Leads directly to caspase-8 activation

(Ligand binds, receptors oligomermise and adaptor protein, eg:FADD, is recruited to receptor via DD interactions)
DED domains on adaptors recruit procaspase 8, forming complex called DISC. the caspases then autoactivate or cross-activate eachother)

Mitochondrial/intrinsic pathway leads to caspase-9 activation

(Caspase 8 can stimulate the mitochondria pathway via Bid activation)

These then cleave the effector caspases: 3, 7, 6 which activates them.
These caspases cleave intracellular substrates to promote cell death eg: cytoskeleton, adhesion proteins…

INTRINSIC PATHWAY
initiated in response to intracellular stress/damage

mitochondrial membrane permeabilisation to release Cytochrome C (and other pro-apoptotic mediators)

this interacts with an adaptor protein Apaf-1 which recruits procaspase-9 via CARD domains forming the APOPTOSOME
As the procaspase-9 are now in close proximity they can transactivate eachother or autoactivate

These then cleave the effector caspases: 3, 7, 6 same as the extrinsic pathway.

60
Q

How is an apoptotic cell cleared up?

L11

A

Following cellular shutdown the cell is broken into smaller pieces: apoptotic bodies which are “bite sized chunks”: (easier for phagocytes to manage)

Dying cells release chemoattractive molecules to recruit phagocytes

Plasma membrane changes (such as caspase related flipping of PS antigen) signal phagocytes to engulf apoptotic bodies

Prevents an unwanted immune response

61
Q

How is apoptosis regulated

L11

A

Regulating extrinsic pathway:

  • Decoy receptors lacking DD meaning adaptor proteins cant bind.
  • c-FLIP competes with caspase 8 to bind to the adaptor protein

Regulating the Intrinsic Pathway:
- Relative levels of pro and anti apoptotic Bcl2 family proteins regulate the mitchondrial outer membrane permiability determining if cytochrome-C is released

  • XIAP is antiapoptotic

p53
phosphorylation of p53 increases its activitly, leading to increased transcription of proapoptotic mediators such as Bax.
May also directly interact with Bcl2 proteins at the mitochondria

62
Q

what changes do you see in an apoptotic cell?

L11

A

Cell is dismantled from inside out.Controlled to minimise damage to nearby cells and avoid immune response
Dead cells are removed by phagocytes

WHAT YOU SEE
Cells round up and detach from neighbours
Blebbing of plasma membrane

Nucleus condensation and DNA fragmentation.
Golgi apparatus, ER, mitochondrion network fragmentation. Mitochondrial outer membrane permeabilisation
Protein cleavage

63
Q

LO: How is apoptosis evaded in cancer?

L11

A

EXTRINSIC PATHWAY

  • Reduced death ligand expression.
  • Decreased expression of the death receptors (eg gene silencing or reduced recycling to membrane after internalised.)
  • impaired activity due to mutations in critical intra-cellular domains.
  • upregulation of decoy receptors that lack the

INTRINSIC PATHWAY
- Loss of functional p53

BOTH
Bcl-2 family dysregulation
- Overexpression of antiapoptotic ie: too much Bcl2
due to mutations(translocations) or epigenetic factors such as promoter hypomethylation.
- deletions or hypomethylation in proapoptotic Bcl2 family proteins

CASPASE ACTIVITY

  • epigenetic silencing leading to reduced expression
  • loss of caspase activity due to mutations.
  • upregulation of inhibitor proteins eg c-FLIP
64
Q

break

A

break

65
Q

Examples of where signaling errors can lead to cancer

L12

A

AMPLIFICATION of an element of the signaling cascade eg:

Ligand - bFGF levels increased in wide array of Carcinomas (either from cancer or microenvironment)

Receptor - increased copies of receptor (by gene amplification, increased transcription, increaded stability, increased recycling after early endosome,…) As with EGFR in colon cancers.

increase amount of transcription factor produced. Myc oncogene seen in most cancers.

ACTIVATING MUTATION eg:

in Receptor - mutation making kinase active regardless of ligand binding in EGFRs in lung cancer.

in Signal propagator - seen in KRAS(lung or pancreas) or BRAF(melonoma, Can be targeted by BRAF inhibitors)

CHANGING EFFICIENCY of protein protein interactions eg
some mutations in p53 or MDM2 can increase their interactions which leads to p53 degredation. (increasing proliferation and decreasing cell death)

EPIGENETIC CHANGES
Methylation of CpG sites in gene promoters can reduce the transcription of the gene,
Histone changes also important

66
Q

How can bFGF be targeted in small cell LUNG cancer?

L12

A

Background:

  • bFGF levels are 100x higher in in lung cancer
  • lung cancers already have over 30x as much expression of XIAP and Bcl-XL(antiapoptotic factors)
  • Adding bFGF results in these levels increasing 5x

Adding bFGF makes cancers more resistant to therapies
(more bFGF in serum, worse therapy outcome)

THERAPY

Targeting the bFGF receptor
eg: FGFR trosine kinase inhibitors given before chemo increase survival in mice with small cell lung cancer.
(inhibits all bFGF receptors)

or another method involving
bFGF ligand traps (injecting antibodies against the ligand)

67
Q

What is Targeted Therapy and why is it useful?

L12

A

Targeted therapy tries to target the subset of receptor that is mutated in a particular cancer rather than the wild type receptor that is found in normal tissues.

results in less side effects of normal tissue

68
Q

Targeted therapy in CML

L12

A

Imatinib in CML

CML is triggered by the formation of the philadelphia chromosome (caused by a translocation of the Kinase ABL gene making it more active )

imatinib is a multi Tyrosine kinase inhibitor specific for the supset of the receptors that are upregulated in the cancer

resistance mechanisms compensate by increasing activity of other kinases
(same effect is seen for most kinase inhibitors: eg treating breast cancer with a MEK inhibitor can result in increase in PDGF receptors)
Changes balance so cell adapts to find a new balance.
Large acute cell death to treatment but some cells will have compensating pathways unregulated and survive

69
Q

Targeted Therapy: EGFR mutation in non small cell Lung cancer

L13

A

about 15% of NSCLC in UK have activating mutation in EGFR driving tumourogenesis

These patients are then treated with an EGFR inhibitor

Good initial results shrinking tumour bu then the tumour reappears and is resistant (after around 6 months)

Important to note that when they tried treating KRAS Mutant NSCLC with the EGFR inhibitor it DECREASED survival

70
Q

Outline some problems with Targeted therapies

L13

A

Resistance is almost inevitable as all the pathways overlap. (more about buying time then a cure)

Cant take a generic approach as
Can’t be used to treat mutations downstream in the same pathway. Example with using EGFR inihibitor for KRAS NSCLC decreased survival.

71
Q

outline p53 function

L13

A

Cellular stress activates p53

Activated p53 influences:
Cell cycle arrest (antigrowth)
Apoptosis
Senescense

p53 is regulated by MDM2 which causes its degredation

loss of function of p53 in most cancers
can be due to:
mutation on p53 so it cant bind to dna/cause transcription
mutation in MDM2 so that it binds more to p53
MDM2 is overexpressed in many malignancies

72
Q

what drugs aim to restore p53 function?

L13

A

Nutlin-1,2 and 3
as it can prevent MDM2 from binding to p53

(MDM2 mutates to become resistant to the nutlins in turn)

73
Q

how do cancer cells avoid immune destruction via PD-1 signalling

L13

A

Some cancer cells activate PD-L1&2 which which signals through PD-1 on the T cells telling them to switch off.

Antibodies to the PD-1 or PD-L1/2 to prevent the signaling between the cancer cell and the T cell

Useful in NSCLC where there is upregulated PD-L1/2

74
Q

Genomic Instability: DNA repair
by prof BOB BROWN

L14

A

Is an enabling characteristic that influences all the other drivers of cancer

PARP inhibitors
A synthetic lethal approach that is targeting something that isnt there (if dna repair has two key mechanisms and one is already mutated in cancer, if we target the other one then the cancer should die)(idealy minimal effect of knocking out each process individually but when both are gone the cell dies)

up to 1 million mutations a day per cell.
Many damage sensors eg p53
Damage sensors lead to either:
DNA repair, Apoptosis, cell cycle checkpoints, Transctiptional response(stress response)

Cells need to repair these in an error free way. (especially stem cells)

BASE DAMAGE REVERSAL

1) Photo-reactivation. single step. Photolyase enzyme splits the pyrimidine dimers.
2) Bases with simple ADDUCTS can be removed by a DNA Glycosylase and replaced with the correct base.
3) simple strand breaks (such as a nick) can be repaired by a DNA ligase.

BASE DAMAGE REMOVAL
(Recognition, removal, resynthesis, religation)

1) Base Excision repair.
(repairs small, non bulky DNA lesions: methylated,
oxidized, reduced bases)
-Damaged base is recognised and removed by a DNA glycosylase.
- Removal of deoxyribose phosphate in the
backbone then follows, producing a gap: an AP site
-Resynthesis with the correct nucleotide. Done by
DNA polymerase using the other strand as a
template.
-Religation of the break in the strand by DNA Ligase

2) Nucleotide Excision Repair
(repairs bulky DNA lesions)
- Recognition by nucleotide excision repairosome
-Removal by incising the strand either side of damage and removal of this strand by an exonuclease.
- Resynthesis by DNA polymerase using opposite strand as template.
-Religation, a DNA ligase binds the synthesized piece into the backbone.
-mutations in this can cause Xeroderma pigmentosum which is linked to skin cancer

3) Mis-Match Repair (arter dna replication)
( base mispairs, short insertions and deletions )
-Recognised by group of repair proteins which can scan DNA and look for incorrectly paired bases
-Removed by exonuclease
-Resynthesis of the repair patch is done by a DNA polymerase
-Religation of remaining single strand break
- Defects linked to hereditary colon cancer.

DOUBLE STRAND BREAK REPAIR (defect in some female breast cancers eg BRCA1 and 2, these are then hypersensitive to PARP inhibitors)

1) Non-Homologous End Joining
(does not depend on sequence and therefore not error free as incorrect ends can be joined)

2) Homologous Recombination
(broken ends are repaired using the information on the intact homologous chromosome)
- Less likely to result in mutations.

SLOPPY COPIERS
Low fidelity DNA polymerase bypasses DNA lesions (that would normally stall normal ones) during dna replication.

75
Q

Types of DNA damage

L14

A

Stalled replication forks, needs to be bypased/eliminated.
Base Damage: Adducts, Pyrimidine dimers, nicks, single strand gap, Double strand breaks.
Crosslinks, Cisplatin introduces cross links that are difficult to repair

76
Q

PARP inhibitors and tumour selective Synthetic lethality

L14

A

Useful in breast and ovarian cancers with BRCA mutations

PARP proteins are key in repairing single strand breaks
BRCA1/2 are key in homologous recombination

PARP inhibitors cause Single strand breaks not to be repaired effectively
This results in more Double strand breaks.

Normal cells can repair this via Homologous recombination so survive.

Cells with mutations in BRCA1/2 have impaired homologous recombination and therefore use more error prone Non-Homologous End Joining which leads to v high levels of chromosomal instability and hence cell death

Selective lethality could also be useful in targeting metabolic tumours

77
Q

What is the mutator phenotype hypothesis?

and what is the alternative hypothesis?
(oncogenes induced replication stress hypothesis)

L14

A

Mutations in DNA repair lead to genomic instability and more mutations in cells that can drive cancer development.

Such genomic instability leads to increased mutation rate at oncogenes and tumour suppressor genes

However in SPORADIC cancer (non inherited) this genomic instability is not very easy to detect.

Alternative hypothesis that these cancers aren’t anything to do with mutated DNA repair and more to do with oncogenes causing DNA REPLICATION STRESS

ie: “oncogenes induced replication stress hypothesis”
Activated oncogenes induce replication stress and hence genomic instability

78
Q

processes of metastasis

L15

A

Subset of primary tumour break through the BM in response to extracellular cues

Leading to local invasion
Followed by intravasculisation
followed by extravasculisation, colonisation and mets.
(They move around the body by hijacking movement capabilities similar to leukocytes and fibroblasts)

Metastases can be dormant for a long time

79
Q

Mechanisms for metastasis

A

Epithelial to Mesenchymal Transition (EMT)
(cells start to lose epithelial characteristics and become more mesenchymal(fibroblast like) cells, ie flat and move around)

Genomic instability means can cause tumour initiation and progression but is not able to explain cancer cells rapid and REVERSABLE differentiation to new phenotypes

NON GENOMIC instability:

Phenotypic changes as a result of biochemicals(GFs, hypoxia, chemo, TME), without mutations in genes, causing a switch between cellular states (also seen in stem cells).
Can hijack systems already used by leukocytes and fibroblasts in wound healing

eg: they can cause transcription of a gene that causes motility which isnt normally transcribed

activation of a signalling pathway (eg EGFR) can lead to to activation of invasion and metastasis via altering levels of TFs that in turn alter expression of genes that are involved in growth and migration (eg: E-cadherin gets downregulated

80
Q

Mechanisms for cell movement

A

INVADAPODIA formation:
cells secrete Matrix degrading Metallo-Proteases to make space infront of invadapodia

Actin protrudes from the invadapodia

Integrins hold extracellular membrane

AMOEBOID MIGRATION
Generates hydrostatic pressure to push cell

81
Q

Tumour vascularsature

A

Blood vessels form so quickly that they arent very tight and v leaky so cancer cells can access v easily

Lymphatic vessels are also easy to get into as they are made for immune cells to use.
Tumour cells can station in lymph nodes and spread through the system

82
Q

What determines distant metastases formation?

A

Seed and soil theory
(seeds carried in all directions but will only grow when land on fertile soil)

Secreted factors prepare the ground:
Premetastatic niche formation via release of cytokines and GFs and exosomes from tumours into the blood prepare sites(soil) for metastasis
eg: osteoclasts can be stimulated by primary cancer to make space for a met.

Mechanical entrapment theory
(The first organ encountered by the circulating cells will be where most stop and consequently where the most metastasis are seem)

Realistically a mixture of both

83
Q

Treatments to control cancer metastasis

A

Targeting the EMT using c-Met inhibitors as c-met is important in reprogramming.
(many drugs in trials)

Inhibiting matrix degrading proteins

Blocking angiogenesis
eg by Avastin (a humanized anti-VEGF monoclonal antibody)

Potentially using tumour circulating traps?

84
Q

Problems with cancer therapies

A

Fail to account for the differences between subpopulations of tumour cells at different stages of progression with different mutations.

Especially apparent with patients with metastatic disease where subpopulations can be different

Therapies kill the the bulk of the rapidly dividing cells around the CSC but leave the CSC behind to repeat

Especially important in platinum therapy where CMC arent killed

85
Q

What is the Warburg Effect?

A

AKA aerobic glycolysis
He observed that that cancer cells exhibit glycolysis to lactate (fermentation) and reduced mitochondrial respiration even in the presence of sufficient oxygen

86
Q

What is the Warburg Effect?

A

AKA aerobic glycolysis
He observed that that cancer cells exhibit glycolysis to lactate (fermentation) and reduced mitochondrial respiration even in the presence of sufficient oxygen, rather than oxidative phosphorylation.

87
Q

list the metabolic changes seen in cancer cells

A

INCREASED:
Glycolysis (and lactate production)
Glutamine uptake and metabolism - used to make lipids from kreb cycle when no oxadative phosphorylation.
Acid production and export
Lipid synthesis
Nucleotide synthesis and folate dependency

88
Q

How metabolism is exploited in cancer therapy

A

Pet scans can monitor uptake of radiolabled glucose, useful to find mets. And monitoiring tumour response to drug treatment

89
Q

What are the drivers for metabolic reprogramming of cancer cells

A
  1. Glycolytic intermediates are used for ANABOLISM in rapidly dividing cells (& mitochondrial)
  2. The need to tolerate hypoxia and oxidative stress
  3. Exporting excess acid is required to survive and promotes invasion and metastasis
    (4. Metabolic signals can promote growth and survival)

=> Driven by the action of oncogenes or loss of tumoursuppressor function

90
Q

what regulates this

A

p53 when functionally activated, reduces the rate of glycolosis via regulating transcription of TIGAR

p53 also increases some aspects of oxidation phosphorylation

Metabolic enzyme can act as a tumour suppressor.
Some kreb cell enzymes are tumour suppressors, where loss of function in these genes is associated with cancers as they lead to increased HIF1alpha

91
Q

Summarise metabolic profiling

A

uses NMR and Mass spec to measure the metabolite compostions.

Can be used to find associations between certain metabolites and cancer

can be used to make sure you have clear margins in surgery

92
Q

How does obesity lead to cancer

A

Metabolic aspects:
insulin resistance leads to higher insulin levels which drive growth eg in breast cancer.

Aromatase activity in adipocytes can produce hormones (oestrogen) which can increase risk of some cancers

93
Q

What causes some tumour cells to become invasive?

A

Single cell genetic profiling revealed that the cells that are invasive in a tumour have the same genome as the other non invading cells

ie; what causes a cell to become invasive isn’t a particular mutation.

could be: Epigenetic, metabolic, stromal influences

94
Q

Cancer Stem Cells (CSC)

A

there are 2 models for CSC

1- All cancer cells are potential cancer stem cells but have a low probability of proliferation in clonogenic assays (ie ASSAYS LIMIT PROLIFERATION)
(any cancer cell can be a CSC if its in the right environment.

2 - Only a small definable subset of cancer cells are cancer stem cells that have the ability to proliferate indefinitely

Will discuss model 2 in depth:

Rare cells within tumors with the ability to selfrenew and give rise to the phenotypically diverse
tumor cell population to drive tumorigenesis

Common properties shared with stem cells:

1 ) Assymetric Division leading to

  • self renewal
  • differentiation into phenotypically diverse cell types which lack unlimited proliferation.
    2) both are resistant to DNA damage
    3) Similar pathways regulate self renewal (disregulated in CSC)

originally idea came from finding that only a very small subset of cancer cells have self renewal capacity and hence are capable of forming new colonies.

  • Therefore need high numbers of tumour cells transplanted to form a new tumour.
  • Yet some subpopulations(CSC) can cause new colonies with much lower numbers

Some markers of normal stem cells can identify these populations of CSC that will make tumours more readily when transplanted into mice (using as few as 10 cells)
making model 2 more likely.

(the two models can also be combined, where additional CSCs may arrise due to clonal evoloution from either mutations or epigenetic modifications. If the new CSC is more aggressive it can become dominant and drive tumour.)

CSC can explain why some ovarian tumour relapses respond to the same drug again and some do not

95
Q

Metastatic cancer cells qualities

A

• Cells arrest in the capillary beds of distant
organs
• Extravasation into distant organ
• Survival and proliferation in target organ
– Depends on multiple interactions (“cross-talk”)
between tumor cell and organ
microenvironment.

must be Migratory CSCs
(if we can stop CSC then maybe we can stop metastasis)

96
Q

What are micro RNAs

A

regulate TRANSLATION of genes.

MicroRNA’s (miRNA’s) are small (about 20nt) noncoding RNA molecules that regulate eukaryotic gene expression at the TRANSLATION level.
(are a type of RNAi)

Can form RNA-induced Silencing Complexes (RISC) which can silence multiple genes

RNAi binds to Dicer (an endonuclease protein) that cuts the miRNAa into short segments

(These short segments then bind an argonort protein
One guide strand remains bound to argonort and the other is destroyed )

this along with other proteins forms the RNA-induced silencing complex (RISC)

FOR siRNA:
siRNA results in precise binding of risk complex to exact sites on mRNAs (determined by base pairing)
Argonort cleaves mRNA which then gets degraded

FOR miRNA:
miRNA sequence also guide RISC to mRNAs however usually only part of the miRNA (seed region) pairs to the target mRNA.
imprecise matching allows miRNAs to target many different mRNAs.
Can result in inhibiting translation or degrade mRNA.

FUNCTION: to block gene expression by:

1 - Inhibition of translation

2- mRNA degradation

97
Q

micro RNAs and cancer

A

Can be a tumour suppressor or oncogene or both.

Can act as either a tumour suppressor by binding to oncogene mRNA
(Suppress expression of oncogenes, growth promoting, survival and angiogenic genes)

or as an oncogene by binding to tumour suppressor gene mRNA
(Suppress expression of tumor suppressor, growth inhibitory, proapoptotic genes)

But, the same miRNA can be oncogenic in one tumour and tumour suppressive in a different tumour

miRNAs can also alter the cells epigenome by inhibiting DNA methyltransferase or regulating histone methyltransferase.

miRNAs have been shown to be involved in every cancer hallmark

Many different miRNAs can effect many parts of the same pathway.

Dysregulation of miRNAs can result in inappropriate proliferation

TP53 can regulate multiple miRNAs.
MiRNAs can target TP53 mRNA.

TP53 regulated MiRNAs can target (and inhibit translation of) MDM2, the negative regulator of TP53, increasing its own levels

MYC is directly involved in the transcriptional silencing of multiple miRNAs which normally would have antiproliferative, antitumourigenic and pro-apoptotic activity.

Can be useful as biomarkers as they are secreted into the circulation and are measurable in serum, plasma and other body fluids.

98
Q

Summary of micro RNA

A

MiRNA is coded within the genome and exist as single genes or gene clusters.

The miRNA gene transcripts are sequentially processed (pri- then pre-miRs and finally mature miRNAs).

Mature miRNAs are short non-coding RNA molecules of 19-22nt.

They are post-transcriptional regulators of mRNA, estimated to regulate at least one third of all human genes.

Altered microRNA expression profiles are associated with a variety of diseases, including cancer.

MiRNAs can operate as oncogenes or tumour suppressor genes, influence cancer pathways and drive the cancer process.

MiRNAs are potential biomarkers of disease (including cancer) and have significant potential as prognostic tools and present therapeutic opportunities.

99
Q

Examples of targeted therapies

A

https://www.cancer.net/navigating-cancer-care/how-cancer-treated/personalized-and-targeted-therapies/understanding-targeted-therapy

100
Q

difference between chemo and targeted

A

https://www.sinobiological.com/the-differences-between-chemotherapy-and-targeted-therapy.html

101
Q

oncogene addiction

A

https://www.cell.com/current-biology/fulltext/S0960-9822(11)01253-X

102
Q

Hormone therapy

A

some tumours use hormones to fuel their growth
eg estrogen or progesterone

Tamoxifen is a drug that blocks oestrogen from binding to breast cancer cells.
lowers the risk of recurrence

Aromatase inhibitors decrease the amount of estrogen made in tissues other than the ovaries in postmenopausal women by blocking the aromatase enzyme. This enzyme changes weak male hormones called androgens into estrogen when the ovaries have stopped making estrogen during menopause

Ovarian suppression. Ovarian suppression is the use of drugs or surgery to stop the ovaries from producing oestrogen. It may be used in addition to another type of hormonal therapy for women who have not been through menopause. There are 2 methods used for ovarian suppression:

Drugs such as gonadotrophin
surgical removal

103
Q

Targeted therapy

A

Targeted therapy is a treatment that targets the cancer’s specific genes
blocks the growth and spread of cancer cells while limiting damage to healthy cells

monoclonal antibodies and small molecule inhibitors of the HER2 receptor

104
Q

examples of targeted therapy

A

monoclonal antibodies for HER2 positive breast cancer

hormone therapies for oestrogen positive cancers

immuno therapy eg car T cells b cell ALL cd19

VEGF inhibitors

PARP inhibitors for cancers with defect holologous recomnination

105
Q

more targeted therapies

A

HER2 is upregulated in breast cancer, can use monoclonal antibodies or small molecule inhibitors to block

EGFR may be overexpressed lung or colorectal cancers and can be targeted

same for vegf.
tyrosine kinase inhibitors can be used to target the receptor and monoclonal antibodies can target the

BRAF mutations in over half of melanomas using B-Raf enzyme inhibitors or MEK inhibitors

bFGF in small cell lung cancer FGFR trosine kinase inhibitors given before chemo increase survival in mice with small cell lung cancer.
(inhibits all bFGF receptors)
or another method involving
bFGF ligand traps (injecting antibodies against the ligand)

Mod 1 (2 decks)

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