How do Cancers Grow? Flashcards Preview

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Flashcards in How do Cancers Grow? Deck (24)
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1
Q

What is meant by the ‘Hayflick limit’?

A

The limit of the number of times a cell can divide before reaching senescence; 20-60 times in culture.

2
Q

What is a telomere?

A
  • Repetitive region at the ends of chromosomes
  • Protects the end of the chromosome from degradation/fusion w/neighbouring chromosomes
  • Like the plastic bit at the end of shoelaces
3
Q

How do cancer cells have replicative immortality?

A
  • Each time a cell divides, its telmomeres become shorter to the point of senescence, where the cell can no longer divide. The cell eventually dies.
  • Where a normal cell has its normal cell cycle checkpoints disrupted (e.g. p53 loss), the cell keeps on dividing past senescence till they reach a ‘Crisis’ stage
  • Most cells die at Crisis (chromosomes are unstable with minimal telomere protection, start to fragment), however some survive due to mutation by activating telomerase (90%) (restoring telomeres) or ATL (10%).
4
Q

What cells are telomerase normally expressed in?

A
  • Germ cells (sperm/egg - chromosomes can’t be shorter than our parents)
  • Stem cells
  • 90% of malignant cells; achieving Hallmark of Replicative Immortality
5
Q

What is Alternative Telomere Lengthening?

A
  • At crisis, the cells that haven’t mutated to express telomerase, fusion/recombination occurs between the ends of different chromosomes to create new telomeres
  • Leading the chromosomal rearrangements; fusions, deletions, amplifications, duplications.
  • 10% of cancer cells
6
Q

How do cells ‘know’ what to do? E.g. divide, grow, rest, die, differentiate, move?

A
  • They sense the environment and respond appropriately, changing gene expression (signals transduced to nucleus)
  • They receive chemical messages (growth factors, mitogens, cytokines, hormones, nutrients, AAs, O2, CO2)

> If this goes wrong, it can lead to uncontrolled proliferation and cell survival.

7
Q

What are the key features of receptor signalling?

A
  • Specificity (ligand-protein, protein-protein)
  • Signal amplification
  • Signal convergence
  • On cell surface or intracellular
  • End result: change in gene expression
8
Q

What types of receptor are there?

A
  • Enzyme coupled receptors e.g. receptor tyrosine kinases (RTKs, such as EGFR; epidermal growth factor receptor, vascular- VEGFR)
  • Steroid hormone receptors (nuclear receptors) e.g. estrogen
  • GPCRs; not currently target of many anti-cancer drugs despite being a popular drug target in other diseases
9
Q

What is EGFR, and what does it do?

A
  • Epidermal growth factor receptor (a tyrosine kinase receptor)
  • Senses growth signals (e.g. EGF)
  • Leads to increase in proteins required for cell division (proliferation; mutation = bad)

Composed of:

  • Extracellular ligand-binding domain
  • Transmembrane domain
  • Kinase domain
10
Q

Describe the EGFR signalling pathway WRT RAS.

A
  • EGF peptide binds to EGFR
  • Conformational change; exposes dimerisation domain (for another EGFR/another protein)
  • EGFR auto- and trans-phosphorylates; each other (fellow EGFRs) and themselves
  • RAS is activated
  • Activates RAS-RAF-MEK-ERK pathway phosphorylating each other as an “on”/”off” switch; communicates signal of EGF peptide to DNA in nucleus
  • ERK (extracellular signal-related kinase) is a transcription factor/inside the nucleus, switches on 100 genes for cell division = greater proliferation
11
Q

Describe the EGFR signalling pathway WRT PI3K.

A
  • PI3K; kinase, of the 3’ position
  • Activation of PI3K phosphorylates and activates protein AKT (localising it in the plasma membrane)
  • Whole process happens outside of the nucleus; there is no change to DNA
  • Pathway downregulates p53, switching off/reducing apoptosis
  • Thus promoting proliferation
12
Q

What are some examples of EGFR mutations?

Give an example.

A
  • Frequently mutated in cancers
    > Change in DNA
    > Change in protein sequence
    > Change in protein function

> > > E.g. EGFR permanently activated; behaving as if bound to EGF (even in its absence), promoting cell division even when no growth signal is present.

13
Q

What drugs target EGFR and what are their modes of action?

A

Cetuximab:
- Stops EGF binding to EGFR; an antibody that binds to the extracellular domain of EGFR, blocking the receptor

Erlotinib, Gefitinib:

  • Stops EGFR activation; drugs look v. similar to ATP (which is required for activation), but doesn’t behave like ATP, blocking activation
  • Binds to kinase domain, inhibiting auto/trans-phosphorylation.
14
Q

What is the ‘silver lining’ to an overexpressed, mutated EGFR WRT treatment?

A
  • Same EGFR mutations that promote cancer also make EGFR more sensitive to erlotinib and gefitinib
15
Q

What is a cancer patient’s DNA sequence determined?

A
  • To decide which drug to use; e.g. if EGFR mutated, then cetuximab may be ineffective
  • Personalised medicine
16
Q

What are the issues surrounding evolution & resistance of EGFR WRT erlotinib anti-cancer therapy?

A
  • Mutations can cause sensitivity or resistance to drugs
  • Mutations in EGFR can cause resistance to drug (e.g. erlotinib) treatment; e.g. if the kinase domain of EGFR (drug target of erlotinib) were to mutate, the drug would no longer be able to bind to EGFR and block activation (competitive inhibition over ATP)
  • There is a good chance of mutation at the drug target
17
Q

Would a mutation downstream in the RAS-RAF-MEK-ERK pathway yield resistance to erlotinib treatment?

A
  • If RAF (downstream of RAS) was mutated and constantly switched on (phosphorylated) for example, this would lead to uncontrolled division/proliferation
  • Binding of erlotinib at EGFR would hence be futile if a mutation occurred downstream
  • RAS is over-activated in smokers
18
Q

Why is combination therapy used?

A

Combination therapy means it is more difficult for cancers to become resistant

19
Q

What are steroid hormone receptors? (derived from? which superfamily? examples?)

A
  • Derived from cholesterol (a membrane component)
  • Can diffuse into cells; no need for cell surface receptors
  • Part of the nuclear receptor superfamily
  • Transcription factors which become activated by steroid hormones (proteins that bind to DNA to switch on/off genes)
  • E.g. estrogen receptor (ER), androgen receptor (AR), progesterone receptor (PR), retinoic acid receptor
20
Q

What is the estrogen receptor an example of, and what occurs upon ligand binding?

A
  • Type I steroid hormone receptor (activated in cytoplasm, not nucleus)
  • Ligand (estradiol/estrogen) diffuses into cell
  • Binds to (monomer) receptor, displacing associated chaperone proteins e.g. HSP90 (heat shock protein 90)
  • ER is phosphorylated
  • ER dimerises (w/another ER) and migrates to nucleus
  • ER dimer then associates w/co-activators (AF1 or AF2) or co-repressors, modifying transcription of target genes
21
Q

What is Tamoxifen, why does it need to be metabolised, and what is its mechanism of action?

A
  • Selective ER modifier (SERM; it can be estrogenic)
  • Estrogen antagonist (recruits co-repressor to domain AF), but with some agonism (upregulation of ER/estrogenic in uterus & bone = cancer risk, as ER has 2 activator domains; still recruits co-activator to AF1)
  • Mostly anti-estrogenic effect though (AF2)
  • Is a pro-drug; metabolised to active metabolites by CYP2D6 (of CYP450 superfamily)
22
Q

What is Fulvestrant and how does it differ to Tamoxifen?

A
  • Selective ER down-regulator (SERD)
  • “Pure” anti-estrogen (no agonism; unlike agonism w/Tamoxifen of uterus & bone)
  • Prevents dimerisation, thus no activation (ER dimer dissociation means ER never reaches nucleus)
  • Increases degradation of ER
  • Thus no transcription, no activation of estrogen-sensitive gene
23
Q

What are the general principles of signalling in cancer?

A
  • Phosphorylation cascades
  • Pathways interact
  • Gene expression is altered
  • Abnormal signalling seen in cancers = abnormal proliferation/survival
  • Signalling can be target for therapy
24
Q

What is meant by constitutive activation?

A
  • A constantly activated protein irrespective of whether there is a ligand stimulus present
  • Can be EGFR or downstream protein e.g. RAF, or both