1) The Molecular Biology of Cancer
What is ‘Cancer’? –
Disease characterised by uncontrolled cellular proliferation leading to invasion of
surrounding tissues & spread/metastasis to distant regions of the body
Benign tumour (non-cancerous) ‘Gentle & kind’
Neoplasm
Malignant tumour (cancerous) ‘Evil’
What makes normal cells cancerous? –
6 properties that underlie the development of almost all cancer cells
1) Self-sufficiency in growth signals –
Normal cells are required to grow + divide in a controlled manner
E.g. during development, tissue homeostasis, wound healing,
immune reactions
They receive external signals (e.g. growth factors, hormones, cytokines)
Tell them to activate growth pathways
FGF
PDGF
When signals stop, normal cells stop growing
Cancerous cells can produce their own signals or have permanently active receptors
+ growth pathways
E.g. EGFR, MAPK pathway
They no longer need external stimuli to grow – they are SELF SUFFICIENT
Many pronto oncogenes fall into this category
, 2) Insensitivity to anti-growth signals –
Control of cell growth = multi-layered
Growth (+) signals
Anti-growth (-) signals
Anti-growth signals activate cell cycle checkpoints
Stop cell from dividing
Checkpoints act as ‘brakes’ to stop cell division if there is problem (e.g. DNA
damage, chromosomal instability)
TGF-β = anti-growth signal
These signals usually act to keep the Retinoblastoma protein active
Keeps brakes on cell division
Rb = tumour suppressor gene
3) Evading apoptosis –
Apoptosis = programmed cell death
Organised & efficient
Gets rid of damaged/unwanted cells
Signals come extrinsically (outside the cell) or intrinsically (inside the cell)
Cell bsc commits suicide
Cancerous cells normally disrupt + evade intrinsic apoptosis pathway
Frequently by mutation of p53 (a gatekeeper)
Or overexpression of anti-apoptotic proteins (BCL2)
p53 = ‘guardian of the genome’ = tumour suppressor gene (is mutated in half of all
cancers)
4) Limitless replicative potential –
Cells contain a timer
Keeps track of their age (how many times they’ve divided)
Most cells only divide a limited number of times
HAYFLICK NUMBER
After 40-60 divisions the cell stops dividing + enters senescence
Molecular clock = telomeres that cap the chromosome ends
With each replication, some telomere DNA is lost
When all the telomere is lost, the cell stops dividing
Cancerous cells reverse telomerase loss by activating ‘Telomerase’ enzyme or
‘alternative lengthening of telomeres’ pathway
Immortality comes at a price as DNA damage increases
What is ‘Cancer’? –
Disease characterised by uncontrolled cellular proliferation leading to invasion of
surrounding tissues & spread/metastasis to distant regions of the body
Benign tumour (non-cancerous) ‘Gentle & kind’
Neoplasm
Malignant tumour (cancerous) ‘Evil’
What makes normal cells cancerous? –
6 properties that underlie the development of almost all cancer cells
1) Self-sufficiency in growth signals –
Normal cells are required to grow + divide in a controlled manner
E.g. during development, tissue homeostasis, wound healing,
immune reactions
They receive external signals (e.g. growth factors, hormones, cytokines)
Tell them to activate growth pathways
FGF
PDGF
When signals stop, normal cells stop growing
Cancerous cells can produce their own signals or have permanently active receptors
+ growth pathways
E.g. EGFR, MAPK pathway
They no longer need external stimuli to grow – they are SELF SUFFICIENT
Many pronto oncogenes fall into this category
, 2) Insensitivity to anti-growth signals –
Control of cell growth = multi-layered
Growth (+) signals
Anti-growth (-) signals
Anti-growth signals activate cell cycle checkpoints
Stop cell from dividing
Checkpoints act as ‘brakes’ to stop cell division if there is problem (e.g. DNA
damage, chromosomal instability)
TGF-β = anti-growth signal
These signals usually act to keep the Retinoblastoma protein active
Keeps brakes on cell division
Rb = tumour suppressor gene
3) Evading apoptosis –
Apoptosis = programmed cell death
Organised & efficient
Gets rid of damaged/unwanted cells
Signals come extrinsically (outside the cell) or intrinsically (inside the cell)
Cell bsc commits suicide
Cancerous cells normally disrupt + evade intrinsic apoptosis pathway
Frequently by mutation of p53 (a gatekeeper)
Or overexpression of anti-apoptotic proteins (BCL2)
p53 = ‘guardian of the genome’ = tumour suppressor gene (is mutated in half of all
cancers)
4) Limitless replicative potential –
Cells contain a timer
Keeps track of their age (how many times they’ve divided)
Most cells only divide a limited number of times
HAYFLICK NUMBER
After 40-60 divisions the cell stops dividing + enters senescence
Molecular clock = telomeres that cap the chromosome ends
With each replication, some telomere DNA is lost
When all the telomere is lost, the cell stops dividing
Cancerous cells reverse telomerase loss by activating ‘Telomerase’ enzyme or
‘alternative lengthening of telomeres’ pathway
Immortality comes at a price as DNA damage increases
