Hallmarks of cancer Flashcards
What are the TWO common types of tumour suppressor
p53 and RB1
What is the Role of p53?
- p53 is a transcription factor which blocks the cell cycle in response to cellular damage
- Induces apoptosis if DNA is irreplaceable
- Leads to changes in gene expression
- Most commonly mutated gene in cancers
What is the role of RB1?
Blocks the cell cycle by binding and
inhibiting E2F transcription factors which means the cell cycle cant proceed past G1/S
-RB1 itself is inhibited by phosphorylation (via cyclin D-CDK4) which releases E2F transcription factor which can go on to express genes.
What conditions activate p53?
- Low oxygen
- DNA damage
- Chemotherapeutic agents
- Other stress
What are the TWO types of Proto-oncogenes
MYC and RAS
What is MYC?
This is a transcription factor which partners with MAX and promotes cell growth therefore leading to changes in gene expression
What is RAS?
- This is a G protein which binds to GDP when inactive and GTP when active
- Activated by growth factors and activates downstream signalling pathways= gene expression
What 4 factors can cause cell death?
Damage, infection, ischaemia or cancer
How does intrinsic apoptosis occur?
When there is internal damage apoptosis occurs though the mitochondrial pathway. Cytochrome C is released from the mitochondria and activation of the capase cascade occurs.
How does extrinsic apoptosis occur?
This process is usually activated by the immune system via the Fas/FasL or TNf/TNF-R1 receptors and then activation of the capase cascade
What is the capase cascade?
consists of cystine proteases causing cleavage of proteases and then organised cell disassembly
How are cancer cells resistant of apoptosis?
Upregulation of survival signals Bcl2 and down regulation of pro-apoptotic signals Bax
What is necrosis?
pro-inflammatory signals released and imune cells recruited which can promote angiogenisis growth factors released which promote proliferation. BUT necrosis is not always good as can promote cancer. This is more lysis and affects groups of cells not a singular one.
Why are telomeres important in mortality?
Telomeres are the repetitive sections at the end of a chromosome and each time a cell divides the telomere gets shorter, unless telomerase is active to restore them.
Where is telomerase normally found?
In germ cells or stem cells
Do normal cells have telomeres?
No, telomeres shorten after each division until they cease to work leading to senescence
What is Alternative Telomere lengthening?
Cells don’t express telomerase,
Fusion between ends of different chromosomes.
these are oncogenic changes
What does EGFR stand for?
Epidermal Growth Factor Receptor
What does EGFR do?
Senses growth signals and leads to increased proteins needed for cell division through the RAS/RAF/MEK/ERK pathway or the PI3K pathway
How do we normally deactivate the EGFR signalling?
- Phsphotases used to remove kinases
2. Turn off RAS proteins
What drugs target EGFR signalling by inhibiting binding of EGF?
Cetuximab an antibody that blocks the receptor
What drugs inhibit EGFR activation and therefore signalling?
Erlotinib and Gefitinib, they look like ATP (which is required for activation of EGFR) but don’t behave like ATP
Why is combination anti-cancer therapy so effective?
For resistance against two or more therapies, multiple mutations must occur in the same cell and much less likely to occur quickly enough
Give 4 examples of steroid hormone receptors
estrogen receptor, androgen receptor, progesterone receptor, retonic acid receptor
What is the MOA for an estrogen receptor being activated?
This receptor is activated in the cytoplasm where the ligand -estradiol diffuses into the cell and binds to the receptor displacing chaperone proteins and this dimerising, migrating into the nucleus. The dimer associates with co-activators or co-repressors to modify transcription of target genes.
What is the MOA for Tamoxifen
Metabolised to active form by CYPD26 and then binds to ER with a much higher affinity than estrogen and is an antagonist for estrogen mostly in the breast but in bone and uterus can be agonist. This is a SERM
How does Fulvestrant work?
Anti-estrogen (NOT SERM) prevents dimerisation/ activation and increases degradation delevtive ER down regulator (SERD)
How do cancer cells achieve REPLICATIVE IMMORTALITY
Reactivating telomerase (90% of cancer cells)
What histone deacetylase inhibitors are available?
Vorinostat, Romidepsin and Panobinostat
Hw can transcription be affected??
Changes in protein levels, changes in DNA structure, changes in DNA sequence
What is p53?
This a tetramer which is a transcription factor, it binds to target promoters to regulate transcription
What can mutations in RB tumour suppressor cause?
missed exons
What is the role of microRNAs?
Repress gene expression, mutations of them can cause dysregulation!
How do cancer cells acquire the vast amount of protein needed to proliferate?
Oncogenic mutatations increase activity and abundance of ribosomes and translation factors via PI3K/MTORC pathway
What does ubiquination do?
Tags proteins that are no longer needed for degradation by proteasome
What does MDM2 do?
Targets P53 for ubiquitinisation via proteasome
How is cancer genetic?
with two or more mutations for example RAS like oncogene in the cytoplasm and MYC like oncogene in the nucleus.
Give an example of a point mutation
P53 and RAS - changes in siingle nucleotides have dramatic effects on protein function
Give an example of a deletion mutation
EGFR and INK4 removal or regions of DNA can inactivate genes and lead to truncated proteins
Give an example of amplification mutations
MDM2 Increase the number of copies of a gene and also reduces the amount of p53 as ubiquitinates p53
Give an example of a translocation mutation
Philadelphia chromosome- give rise to fusion proteins due to rearrangement of chromosomes by juxtaposing bits of genes.
What is BCR and ABL?
BCR is a threonine kinase and GTPase
ABL is a signalling tyrosine kinase
What drugs target BCR ABL?
Imatinib, Nilotinib, Dasatinib all tyrosine kinase inhibitors.
Why is chronic inflammation a major risk factor for cancer?
Promotes mutagenisis (RNS and ROS produced during inflammation) Promotes tumour progression and metastasis.
How does smoking cigarettes cause cancer?
p53 and KRAS mutations
Hoes does infection cause cancer?
Insertion of the viruses own genome int the cell causing the cell to grow out of control
Long term inflammation can cause changes
Some infections can suppress the person’s immune system and their immune system normally is a barrier to contracting cancer.
How does HPV virus cause cancer?
Produces oncogenic proteins E6 which targets p53 for degredation and E7 which interacts with RBP protein.
How does Hwlicobacter pylori cause cancer
Causes ulceration which it chronic inflammation and increases ROS and RNS in the stomach and free radicals cause DNA damage =mutation. Can result in gastric carcinoma and malt lymphoma.
How does radiation cause cancer?
Ionising radiation can dislodge electrons this can damage DNA by causing double stranded breaks or by producing free radicals that can attack DNA
How does UV cause cancer?
cyclo pyrimidine dimers and 6-4 photoproducts between adjacent pyrimidine bases
What other environmental mutagens are there?
occupational chemicals, natural products such as fungal toxins, medical mutagens such as chemo and atmospheric particles from vehicle exhaust
How is obesity a risk factor for cancer?
Fat cells produce estrogen and other hormones, also inflammatory signals and recruitment of immune cells
How does alcohol cause cancer?
There is no safe limit risk increases with intake, mouth throat, bowel ect. Alcohol is converted to acetylaldehyde which can damage DNA and inflammation of liver and can lead to generation of ROS and increas estrogen levels.
How does physical activity reduce risk of cancer?
Affects hormone levels reducing insulin and estrogen lowering risk of breast and uterine cancers
Also, exercise moves potential carcinogens down the digestive tract quicker e.g. processed meat and alcohol.
Does pregnancy reduce breast and ovarian cancer risk?
YES
What are the inherited mutagens associated with predisposing individuals to breast cancer?
BRCA1 and BRCA2 (gives a 5 times higher risk)
Under which condition can mutations in tumor supressor genes and oncogenes be inherited?
if they were present in germ cells
Are cancer genetic or inherited?
Genetic
What are the barriers to gene therapy?
commercial barriers (material costs, licence and patent costs) Biological barriers ( many genes mutated variation within tumours requires majority of cancer cells to be affected- can't change every cell in a cancer but can change a gene)
What are the four option for microRNA therapies?
anti-miRs to inactivate oncomirs
microRNA smonges to mop up oncomirs
microRNA mask to block oncomirs
upregulation of tumour supressor miRs (oligonucleotides to mimic TS miRs)
What is an an antagomir
oligonucleotide complimentary to target miR
What barriers are there to successful microRNA therapy?
olig-nucs only last a few mins in blod stream… stability issue, excretion issue as bind to albumin they are of large size and polarity so difficult to cross cell membranes. Biologically high doses of anti mirs are required per miR and they have many targets so might not get to right target also transient inhibition so repeated doses needed
What are Monoclonal antibodies used for?
Make cells visible to the immune system, stop cells dividing, target therapies, diagnosis.
How does Rituximab work?
targets CD20 on B cells which causes antibody mediated cytotoxicity which kills lymphomas and leukaemias
How could we use MABs as delivery systems for therapy?
Radioimmunotherapy, antibody drug conjugates and antibody directed enzyme pro drug therapy
What are the advantages of MABs?
good specificity large quantities well defined purity
Recombinant MABs reduce immun response problems
Can remove Fc region to make smaller
Disadvantages of antibody fragments
reduced circulation half life controlled by Fc region
reduced binding activity
loss of immune effector region
What is the role of cancer vaccines?
To modify the cancer patient’s immune system to fight cancer via induction of cytotoxic T lymphocytes
