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Flashcards in Molecular Biology Deck (55)
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1
Q

What are the 4 phases of the cell growth cycle?

A

G1

S

G2

M

2
Q

Name some of the characteristics of tumour angiogenesis

A

Uncontrolled expression of pro-angiogenic factors

Disorganised vascular structure (lack of pericytes often)

Low integrity vessels that can collapse, causing hypoxia

Leaky microvasculature

3
Q

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

A

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
Q

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

A

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
Q

What are the 4 stages of asymmetric cell division?

A

Stem cell (totipotent)

Restricted potential stem cell (multipotent)

Progenitor cell (unipotent)

Terminally differentiated cell

6
Q

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

A

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
Q

What part in cancer does Telomerase play?

A

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
Q

How does p53 work?

A

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
Q

What are 3T3 cells?

And what happens when they become transformed?

A

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
Q

What is retinoblastoma?

A

A tumour in the retina

Recessive

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

11
Q

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

A

Glivec (imatinib)

Driven by c-kit receptor activity

12
Q

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

A

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
Q

What is VEGF-VEGFR?

A

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
Q

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

A

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
Q

What is Li Fraumeni Syndrome?

A

An inherited disorder of mutated p53

16
Q

Why can HER2 become constitutively active?

A

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
Q

What is the Philadelphia Chromosome?

A

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
Q

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

A

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
Q

Mutations in what will result in EGFR inhibitors not working?

A

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

20
Q

What are the 3 things that can cause mutations?

A

Chemical carcinogens

Radiation

Viruses (HPV)

21
Q

What is the Src tyrosine kinase?

A

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
Q

What are the functions of the following drugs?

Aflibercept

Bevacizumab (Avastin)

Ramucirumab

A

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
Q

What are the 3 ways of preventing tumour angiogenesis?

A

Inhibiting production of angiogenic proteins

Neutralising angiogenic proteins

Inhibit receptors for angiogenic proteins

24
Q

What type of cells commonly become cancerous?

A

Fast replicating cells such as the epithelium, GI and lungs

25
Q

What are the 3 stages of CML?

A

Initial chronic stage (mild)

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

Acute leukaemic phase (blast crisis)

26
Q

How can resistance to Glivec (imatinib) occur?

A

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
Q

What is C-Abl?

A

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
Q

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

A

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
Q

How does Herceptin (Trastuzumab) work?

A

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
Q

What are the 2 theories for site-specific metastasis?

A

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
31
Q

What 2 things can occur if a mutation occurs in the EFGR?

A

Ligand independence –> Due to constitutive dimerisation - This is the erbB oncoprotein for the EGFR (caused by a deletion)

Over-expression –> Due to gene amplification

32
Q

What does p53 regulate the expression of?

A

p21 cyclin-dependent kinase inhibitor

MDM2 (which inhibits p53)

Bax (a pro-apoptopic protein)

33
Q

What are the 6 different types of tumour suppressor genes (TSGs)?

A

Growth/development suppressors

Cell cycle checkpoint proteins

Cell cycle inhibitors

Inducers of apoptosis

DNA repair enzymes

Developmental pathways

34
Q

How many mutations are needed for a cell to become cancerous?

A

3-7

Often benign cells will be one mutation short of becoming malignant

35
Q

Where do the following cancers arise from?

Carcinoma

Adenocarcinoma

Sarcoma

Leukaemia

A

Carcinoma –> Epithelial cells

Adenocarcinoma –> Glandular tissue (eg, the breast)

Sarcoma –> Connective tissue and muscle

Leukaemia –> Blood cell derived sarcomas

36
Q

Describe the metastatic cascade

A

Primary tumour growth

Angiogenesis

Detachment and invasion into surrounding tissues

Intravasation into lymphatics/capillaries

Survival in the circulation

Arrest in new area/secondary organ

Extravasation into the secondary tissue (lots of cells die at this point)

Establishment of microenvironment

37
Q

What is angiogenesis?

A

The formation of new blood vessels

= neoangiogensis in cancer (driven by hypoxic conditions)

This needs to occur due to the rate that tumours grow, and so they need lots of nutrients and oxygen

38
Q

Explain the Wnt pathway

A

Wnt is a ligand that binds to frizzled sequesters of GSK-3 (a kinase) allowing B-catenin to act as a transcription factor –> Driving cyclin-D and C-Myc expression and so cell proliferation

End result is a loss of function of APC (a tumour suppressor gene), so the inhibitor complex can’t form, allowing B-catenin to be free/active

39
Q

How does HPV cause cancerous effects?

A

Interact with key regulatory proteins

E5 –> Causes prolonged activation of PDGFR

E6/7 –> Inhibit pRB and p53

40
Q

Why does are tumours heterogenous?

A

Due to the asymmetric division of stem cells

41
Q

How does the Hh pathway work?

A

Sonic, Desert and Indian bind to patched TSG, causing the inhibition of the smoothened TSG to be inhibited (so activated)

This causes Gli transcription factors to be released, causing cell proliferation

So LOF of the patched TSG will cause cancer

42
Q

What role does Denosumab have in cancer?

A

It prevents the activation of osteoclasts, which prevents the formation/release of growth factors

43
Q

How does Iressa and Tarceva work?

A

Block ATP, so prevent phosphorylation of kinases

Tarceva only works on hyper-mutated forms of cancer

44
Q

How do you detect if a cancer is HER2+?

A

Immunohistochemistry –> Scale of 0-3 with 3 meaning +ve

FISH ELISA –> Detects the cleavage product in the patients serum

45
Q

How does a loss of function in pRB or p16 affect cell division?

A

pRB –> LOF will remove inhibition (let go) of E2F, allowing it to be constitutively active. This also causes the pathway to be cyclin D/GF independent

p16 –> LOF means that the cycle can’t be stopped to repair DNA, so mutations are passed on to daughter cells and accumulate

46
Q

What are the 3 ways that proto-oncogenes can be converted to oncogenes?

A

All via a gain of function mutation

Point mutation

Gene amplification

Chromosomal translocation

47
Q

What is Ras?

A

Part of EGFR signalling, that can still be targeted after EGFR is constitutively active

Mutations of Ras causes it to always be active, with mutations being different in different cancers (eg, prostate point mutation will be different to that of the lung)

48
Q

What is ADVEXIN?

A

Adenoviral transfer of p53 into a tumour cell

49
Q

How do circulating tumour cells (CTCs) go about extravasation into the secondary tissue?

A

Using selectins, CD44 and integrins to drag the cancer cells through the basement membrane

50
Q

What type of stem cell can become cancerous?

A

Undifferentiated ones that have left their niche

This is because cells need to have the potential to divide to become cancerous

So for a differentiated cell to become cancerous, it must require the ability to differentiate

51
Q

What is leukaemia?

A

A cancer of the white blood cells, which produces tonnes of immature blood cells due to unregulated proliferation

These cells squeeze normal cells out of the bone marrow

Originates from stem/progenitor cells

You can’t get leukaemia of RBCs as they don’t have a nucleus! So no DNA that can be mutated!

52
Q

What’s an EMT?

A

Epithelial to Mesenchymal Transition

This occurs to allow carcinomas to have more motility and be more invasive

53
Q

How are leukaemia’s classified?

A

Either acute/chronic

The site of origin (myeloid or lymphoid)

54
Q

Define Epigenetics

A

Study of changes to an organism in terms of gene expression, as opposed to the alteration of the genetic code

Effects are usually mediated by histone modification (methylation)

55
Q

What is the Cancer Stem Cell Hypothesis?

A

Stem cell niche is expanded

Cancer stem cells then adapt to a different niche…allowing explansion

Cancer stem cells become niche independent, so self-renewal is cell-autonomous

Allows progenitor cells to be converted to cancer stem cells