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Flashcards in Molecular Biology Deck (55)
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1

What are the 4 phases of the cell growth cycle?

G1

S

G2

M

2

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

3

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....

4

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

5

What are the 4 stages of asymmetric cell division?

Stem cell (totipotent)

Restricted potential stem cell (multipotent)

Progenitor cell (unipotent)

Terminally differentiated cell

6

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

7

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

8

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

9

What are 3T3 cells?

And what happens when they become transformed?

Fibroblasts

 

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

10

What is retinoblastoma?

A tumour in the retina

 

Recessive

 

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

11

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

Glivec (imatinib)

 

Driven by c-kit receptor activity

12

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

13

What is VEGF-VEGFR?

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

14

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!

15

What is Li Fraumeni Syndrome?

An inherited disorder of mutated p53

16

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

17

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

18

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

19

Mutations in what will result in EGFR inhibitors not working?

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

20

What are the 3 things that can cause mutations?

Chemical carcinogens

 

Radiation

 

Viruses (HPV)

21

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

22

What are the functions of the following drugs?

 

Aflibercept

Bevacizumab (Avastin)

Ramucirumab

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

23

What are the 3 ways of preventing tumour angiogenesis?

Inhibiting production of angiogenic proteins

 

Neutralising angiogenic proteins

 

Inhibit receptors for angiogenic proteins

24

What type of cells commonly become cancerous?

Fast replicating cells such as the epithelium, GI and lungs

25

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)

26

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)

27

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

28

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

29

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)

30

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