Summary
Samenvatting Mechanisms of Disease 2
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Complete summary of the Mechanisms of Disease 2 (MOD2) course in year 2 Leiden Medicine. Notes from all lectures.
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Samenvatting MOD2HC2 Cancer biology: the hallmarks of cancer
- From healthy to malignant
o Healthy cells / tissues are highly organised (in number and function)
▪ A/B/C – healthy
▪ D/E/F/G – malignant
- Hallmarks of cancer
o Sustaining proliferative signalling
o Evading growth suppressors
o Avoiding immune destruction
o Enabling replicative immortality
o Tumor-promoting inflammation
o Activating invasion & metastasis
o Inducing angiogenesis
o Genome instability & mutation
o Resisting cell death
o Deregulating cellular energetics
- 1. Sustaining proliferative signalling
o Cell proliferation pathway (MAPK
pathway) → this pathway connects receptors
at cell surface to the nucleus where
transcription of genes happens
o Healthy cell: this pathway will not be
activated unless it receives a stimulus from
outside (growth factors) → the availability of
these growth factors is very limited
o Tumor cells: sequester / detach
these signalling pathways with the goal of becoming completely independent (=
sustaining proliferative signalling)
o This detaching of the signalling pathway can be done at different levels of the
pathway:
▪ Overexpression of growth factors (EGF, VEGF)→ tumor cells will start
expressing these growth factors in large numbers
▪ Overexpression of cell surface receptors and/or activating mutations EGFR,
HER2) → by maximising the number of receptors, you can bind all the
potential ligands around the cell + activating mutations that, for example,
activate proteins (e.g. mutation that causes receptors to be constantly
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, active, and thus constantly activate the signalling pathway, without needing
growth factor as a stimulus)
▪ Overexpression of intracellular signalling molecules or activating mutations
(KRAS, BRAF) → same mechanism as above, but then intracellular →
mutations that cause proteins to be constantly active & constantly
phosphorylate subsequent proteins & activate transcription of target genes,
without the need of signals from above (thus leads to independence of
extracellular signals)
▪ Overexpression of transcription factors (MYC, beta-catenin) → by doing this,
a tumor cell becomes completely independent from a signalling cascade
▪ All above named genes promote tumor development once they are
overexpressed or mutated → genes that can stimulate cancer development
are referred to as proto-oncogenes (let op!! Proto-oncogenes are genes
involved in normal cell growth!! Only when mutations in proto-oncogenes
occur, it may become an oncogene which causes the growth of cancer cells)
- 2. Evading growth suppressors
o Healthy cells have a number of mechanisms that are supposed to control
exaggerated cell division
o In healthy cells, the expression of growth suppressor genes is much higher than the
expression of growth promotor genes
o In tumour cells, this balance has shifted → much more expression of growth
promotor cells than expression of growth suppressor cells
o Cell-cycle checkpoints
▪ Important mechanism to keeping cells in check
▪ Start checkpoint: checkpoint between G1 phase and S phase (S phase = DNA
replication) → restriction point in which the cell checks if everything is okay
& if something is wrong with the cell, this checkpoint will stop it from
undergoing DNA replication
▪ G2/M checkpoint: checkpoint between G2 and M phase (mitosis) → to check
if everything is okay before the cell starts dividing
▪ All these checkpoints are major growth suppressors → they stop ‘faulty’ cells
from growing
o Tumour growth
▪ In tumour growth we often see loss-of-function mutations of growth
inhibitors (TGFβ receptor, p16) → tumour suppressor genes
▪ Tumour suppressor genes are normal genes that slow down cell division,
repair DNA mistakes or induce apoptosis (of faulty cells). It is only when loss-
of function mutations occur in these genes → that cells can grow out of
control & lead to cancer
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, o Thus:
▪ Loss of function mutation of growth inhibitors (= tumour suppressors) (TGFβ
receptor, p16)
▪ Gain of function mutations of growth factors (= proto-oncogene) → once
mutation occurs: oncogenes (Cyclin D, CDK4)
o TP53 – the main tumor suppressor gene
▪ TP53 reacts to a variety of extracellular stimuli: hyperproliferative signals,
DNA damage, telomere shortening, hypoxia → all these stimuli activate TP53
▪ TP53 is mutated in > 50% of all human tumors (TP53 = guardian of the
genome)
▪ P53-related pathways affected in > 90% of all tumours
▪ Loss of p53 → loss of cell cycle checkpoints → proliferation of cells with DNA
damage
▪ Some people have a hereditary (heterozygous) mutation in TP53 gene: Li
Fraumeni syndrome → these patients develop multiple primary tumors of
various kinds at a young age. Dominant inheritance
o Wnt signalling pathway
▪ Two main proteins in Wnt signalling pathways:
• APC → tumour suppressor
• β – catenin → oncogene
▪ Healthy cell: APC binds to beta-catenin and destroys it & thus prevents beta-
catenin from entering the nucleus & starting transcription of genes
▪ Tumour cell: tumour cell could have multiple mutations that can lead to
uncontrollable cell growth → most important ones: loss-of-function
mutation in tumour suppressor gene APC or gain of function mutation in
oncogene β – catenin gene.
▪ APC is a main tumour suppressor in colorectal cancer
- 3. Avoiding immune destruction
o Ex: mutation in HLA/MHC class I expression → if tumour cells do not have an MHC
class I molecule, they cannot present any peptides & thus cannot be recognized by T
cells
- 4. Enabling replicative immortality
o Normal cells have limited proliferative capacity
o Once cells have divided a certain number of times → they enter a state of
(replicative) senescence (= aging)
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, ▪ → meaning they have lost the ability to re-enter the cell cycle & generate
daughter cells
o Number of doublings dependent on species, tissue and age of organism →
embryonic stem cells can keep on dividing, but for ex. Adult stem cells and somatic
cells have limited proliferative capacity → somatic cells even worse than adult stem
cells (see graph)
o Human telomeres
▪ Contain 5-15kb of TTAGGG repeats → these repetitive sequences are there
to protect the actual part of the chromosome that is encoding genes and
thus important for cell survival
▪ Telomerase required for their replication
▪ Somatic cells do not express telomerase → thus telomeres shorten over time
→ until it gets to a point where the part of the chromosome that is actually
encoding genes necessary for cell survival, is exposed and can get damaged
▪ So, when the telomeres become extremely short/not present → the cell
receives the instruction to stop dividing (stop cell division)
o Tumours
▪ Tumour cells activate the telomerase gene → so that they can keep their
telomeres long & this thus gives a sort of limitless replicative potential to
cancer cells (they’re not inhibited anymore by the shortening of their
telomeres)
▪ Thus: activation of the TERT (telomerase) is a mechanism by which cancer
stabilizes telomeres
- 5. Activation of invasion & metastasis
o Primary tumours are often not what eventually kills patients → the spreading of
cancer cells throughout the body does. And even in the onset of cancer, it needs
some properties through which tumour cells can invade adjacent tissues
o Mechanisms of cancer cells to invade tissues and spread throughout the body:
▪ Loosening up of tumour cell to tumour cell interactions (inactivation of E-
cadherin)
• In healthy tissues: cells are strictly arranged & communicate with
each other → they can detect if something is wrong with the cell
next to them
• In tumours: loosening of cells & cell interaction
▪ Degradation of extracellular matrix (ECM) (expression of proteolytic
enzymes)
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