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What are the 4 phases of the cell growth cycle?






Name some of the characteristics of tumour angiogenesis

Uncontrolled expression of pro-angiogenic factors


Disorganised vascular structure (lack of pericytes often)


Low integrity vessels that can collapse, causing hypoxia


Leaky microvasculature


How can we target Ras as an anti-cancer therapy?

Due to it having a lipid acid modification that allows it to bind to the membrane, we can inhibit the modification using peptidomimetics

.....These haven't really worked though....


Why is losing the function of tumour suppressor genes (TSGs) more rare?

As they are recessive, so you need to lose both genes to see the effect


Becomes more common if you inherit one recessive gene


What are the 4 stages of asymmetric cell division?

Stem cell (totipotent)

Restricted potential stem cell (multipotent)

Progenitor cell (unipotent)

Terminally differentiated cell


What's the difference between a benign and a malignant tumour?

Benign --> Non cancerous, localised, look like normal cells, surrounded by a fibrous capsule

Malignant --> Grow and divide rapidly, relatively undifferentiated, high nucleus to cytoplasm ratio, less defined border, can become metastatic


What part in cancer does Telomerase play?

Telomerase (reverse transcriptase enzyme) adds tandem repeats to the end of chromosomes to prevent them from being killed


Present in cancer cells and so prevent them from dying naturally....whilst not being present in most somatic cells naturally


How does p53 work?

It is normally complexed to the inhibitor MDM2 protein, rendering it.....inactive

When stressors are present, MDM2 is inhibited, allowing p53 to function


It works as a tetramer, so if one of the 4 units becomes mutated/damaged, the entire thing is non-functional but yet very stable, so it isn't degraded! --> Meaning cells won't die


What are 3T3 cells?

And what happens when they become transformed?



When transformed they have their RAS constitutively active due to a loss of p53, so the cells don't stop proliferating

They also have less cell-to-cell contact, so the chance of them becoming metastatic increases


What is retinoblastoma?

A tumour in the retina




Derived from a single cell (clonal) mutation to do with pRb


What is the main treatment for Gastro-Intestinal Stromal Tumours (GIST)?

Glivec (imatinib)


Driven by c-kit receptor activity


What are the 3 types of immunotherapy that can be used for metastatic cancer?

Ipilimumab --> Blocks CTLA4, enhancing the effects of T cells


Pembrolizumab/Nivolumab --> Block PD1, which increases the immune response by preventing the tumour cells from turning off T cells



A tyrosine kinase receptor that causes downstream signalling leading to angiogenesis


Eg, PI3K/AKT for cell survival

FAK for cell adhesion and migration

Ras --> ERK for proliferation


What are the 4 resistance mechanisms to anti-angiogenic drugs?

Metabolic adaption --> Finding nutrients from places other than the blood vessels


Re-vascularisation --> By expressing other factors like bFGF/PDGF


Co-option of normal peritumoural blood vessels and vascular mimicry --> The tumour cells mimic the endothelial cells


Drugs improve the blood supply --> Which means more nutrients can get to the tumour!


What is Li Fraumeni Syndrome?

An inherited disorder of mutated p53


Why can HER2 become constitutively active?

As the valine (which is hydrophobic and happy in its place) is mutated to glutamine, causing the receptor to close

- Known as the Neu oncoprotein


What is the Philadelphia Chromosome?

In CML there is a translocation between chromosomes 9 and 22, causing 9 to get longer and 22 smaller


BCR becomes partnered with ABL in chromosome 22, which means BCR can't block the kinase domain, meaning cell division can occur


What is TEL-PDGF(B) receptor fusion in CMML?

A translocation between chromosomes 5 (TEL) and 12 (PDGF)


This causes the PFGF kinase to always be active, with the helix-loop region of TEL inducing oligomerisation


Glivec (imatinib) can be used to treat this


Mutations in what will result in EGFR inhibitors not working?

K-Ras, as occurs after the EGFR in the molecular pathway


What are the 3 things that can cause mutations?

Chemical carcinogens




Viruses (HPV)


What is the Src tyrosine kinase?

In a healthy cell the Src genes tyrosine (Y) is phosphorylated, putting it into its inactive form, preventing cell growth....then when needed phosphatase removed it, allowing it to be active


In a cancerous cell the C-terminal tyrosine is mutated/non-existent and so the inactive form cannot be made...leading to a constitutionally active kinase (which drives cell growth)


When constitutively active, the cells have less cell-to-cell contact and so are more likely to become metastatic


What are the functions of the following drugs?



Bevacizumab (Avastin)


Aflibercept --> A fake receptor that competes with all VEGFRs for the angiogenic proteins


Bevacizumab (Avastin) --> An anti VEGF-A antibody


Ramucirumab --> An anti VEGFR-2 antibody


What are the 3 ways of preventing tumour angiogenesis?

Inhibiting production of angiogenic proteins


Neutralising angiogenic proteins


Inhibit receptors for angiogenic proteins


What type of cells commonly become cancerous?

Fast replicating cells such as the epithelium, GI and lungs


What are the 3 stages of CML?

Initial chronic stage (mild)


Accelerated phase that develops after 4 years (when diagnosis usually occurs)


Acute leukaemic phase (blast crisis)


How can resistance to Glivec (imatinib) occur?

Resistance builds by BCR-ABL over-expressing


Point mutations mean that it can't bind, due to its specificity --> Nilotinib/Dasatinib then needed


No drugs are active against the T315I mutation! (except experimental JAK-2 inhibitors)


What is C-Abl?

A non-receptor protein tyrosine kinase


It has a nuclear internalisation and is activated by DNA damage


Interacts with p53 and Rb to regulate gene transcription


Glivec (imatinib) inhibits this kinase by starving it of ATP


What are the 3 ways that we can target the metastatic cascade?

Seeding --> invasion/extravasation/EMT


Dormancy --> Keep the cells dormant for as long as possible, or activate them to kill them


Metastatic colonisation --> Target the signalling pathways for this


How does Herceptin (Trastuzumab) work?

Binds to HER2+ cells, attracting the immune system (via its Fc region) to kill the cell

Also uncouples Src activation, increases p27 expression and promotes Antibody Dependent Cellular Cytotoxicity (ADCC)


What are the 2 theories for site-specific metastasis?

First Pass Organ --> They recolonise in the first organ they come to


Seed and Soil Hypothesis --> Will only recolonise in an environment that supports their growth

- Eg, correct growth factors, adhesion factors and selective chemotaxis