the molecular biology of cancer - lecture

how does a cell become a cancer cell generally?

progressive accumulation of mutations

what increases the likelihood of a cell becoming a cancer cell?

cells with a high rate of turnover

what are the 'hallmark' characteristics of a cancer cell? (6)

- evading growth suppressors

- activating invasion and metastasis

- enabling replicative immortality

- inducing angiogenesis

- resisting cell death

- sustaining proliferative signalling

- DNA damage and DNA replication stress

- mitotic stress

- metabolic stress

- evading immune surveillance

- genomic instability

what does angiogenesis involve?

the tumour creating its own blood supply for oxygen and nutrients

which hallmark characteristic is the most significant driver of the other changes (carcinogenesis) in hereditary cancers?

genomic instability

how does genomic instability drive carcinogenesis in hereditary cancers?

increases spontaneous mutation rate

what is meant by genomic instability? (2)

- gross changes in chromosome structure

- high mutation rate

what drives genomic instability in sporadic cancers?

onocogene-induced DNA replication stress

what else does DNA replication stress drive?

evading cell death and senescence

what is the normal cell response to DNA replication stress?

- limiting nucleotide stores

- fragile sites that are difficult to replicate

- RNA polymerase can regulate

what initiates the progression of a normal to cancerous cell?

oncogene activation

what does oncogene activation lead to?

abnormal proliferation

what does abnormal proliferation lead to?

DNA replication stress

what does DNA replication stress lead to?

genome instability

what does genome instability lead to?

- DDR activation

- ATM-TP53-MDM2 inactivation

- further cancer-favouring mutations

what does DDR activation usually result in?

senescence or apoptosis

what does ATM-TP53-MDM2 inactivation result in?

escape from apoptosis/senescence

what do abnormal proliferation along with escape from apoptosis/senescence lead to?

cancer formation

what do the further cancer-favouring mutations lead to?

metastasis

what is inactive p53 bound to?

MDM2

what usually triggers activation of p53?

cellular stress

what are examples of cellular stress? (3)

- DNA damage

- oncogene activation

- hypoxia

- UV radiation

- ionising radiation

what does activated p53 do? (5)

- upregulates MDM2 for negative feedback of p53

- activates p21 which causes cell cycle arrest (G1/S + G2/M)

- activates DNA repair factors

- activates pro-apoptotic factors

- downregulates anti-apoptotic factors

what can p53 allow the cell to do after the cell cycle is arrested?

senescence

or

return to proliferation

what is the main function of p53?

apoptosis

what is the Li-Fraumeni syndrome?

germline mutations in p53 gene - associated with very early tumour onset

what has the original idea of 'adenoma-carcinoma' sequence of CRC progression evolved to?

'vogelgram' of genetic CRC progression

what does the vogelgram of genetic CRC progression involve? (3)

- mutational activation of oncogenes and inactivation of tumour suppressor genes

- changes in at least 4-5 genes for malignant tumour (fewer for a benign tumour)

- tendency towards a preferred sequence of genetic alterations but total accumulations of changes is the most important factor over the order

what causes a change in the normal epithelium and what does it change to?

- APC/b-catenin (loss of function mutation)

- changes normal epithelium to adenoma

what causes a change in the adenoma and what does it change to? (2)

- K-Ras/B-Raf (gain of function mutation)

- changes adenoma to late adenoma

what causes a change to the late adenoma and what does it change to?

- Smad4/TGF-b RII (loss of function mutation)

- p53/Bax (loss of function mutation)

- changes late adenoma to carcinoma

what are the two main types of genomic instability?

- microsatellite instability (msi)

- chromosomal instability

are most sporadic CRCs from microsatellite instability?

no - 85% are from chromosomal instability

is HNPCC associated with MSI or non-MSI?

MSI

is FAP associated with MSI or non-MSI?

non-MSI

what is a microsatellite?

a tract of repetitive DNA made up of 5-50 repeats of short 2-5 base pair sequence motifs

what ideally happens in DNA replication of a microsatellite?

an accurate copy is made

what are the 2 options for DNA replication of microsatellite when there is slippage?

- a loop in the newly replicated strand leads to a gain of 1 repeat

- a loop in the template strand leads to a loss of 1 repeat

are microsatellite (repetitive DNA) or point mutations more common?

microsatellite mutations are much more common (x1000)

what usually happens after single base mismatches or small insertion/deletion loops?

- causes a distortion to DNA structure

- distortion is recognised and cut out

what happens after single base mismatches or small insertion/deletion loops in HNPCC?

there are defects in recognising and cutting out defective DNA - so still gets copied

in FAP what generally happens to the second (non-mutant) allele of APC?

lose the second one by loss of heterozygosity

what does the mutant allele of APC activate?

the Wnt signalling pathway

what does the activation of the Wnt signalling pathway lead to?

nuclear accumulation of B-catenin

what does the Wnt signalling pathway generally do?

drives cells to proliferate

what normally happens to cells moving up the colonic crypt in terms of proliferation?

more proliferative towards the bottom of the crypt, less proliferative towards the top

how is the proliferation of the cells in the colonic crypts controlled?

- at the bottom of the crypt B-catenin is ON

- towards the top of the crypt B-catenin is turned OFF

what happens if there is an APC or B-catenin mutation?

B-catenin remains ON towards the top of the colonic crypts so a polyp may form

what usually happens in the Wnt signalling pathway?

- Wnt activates 'frizzled' protein

- 'frizzled' protein activates 'dishevelled' protein

- 'dishevelled' protein inactivates a complex which releases B-catenin

- B-catenin allows transcription of Wnt target genes

- transcription ON = cell proliferation

what usually happens when there is too much B-catenin?

- excess B-catenin is phosphorylated

- which allows it to undergo ubiquitylation

- B-catenin can then be degraded by proteosome to stop cell proliferation = transcription OFF

what happens when there is a mutation to APC or B-catenin?

- mutation prevents the phosphorylation of B-catenin

- B-catenin does not get degraded

- carries on transcribing Wnt target genes

- transcription remains ON = cell proliferation