Summary
Samenvatting Mechanisms of Disease 2
- Course
- Institution
Complete summary of the Mechanisms of Disease 2 (MOD2) course in year 2 Leiden Medicine. Notes from all lectures.
[Show more]
Seller
Follow
famkew
Reviews received
Content preview
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
1
, 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
2
, 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)
3
, ▪ → 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)
4
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller famkew. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $11.98. You're not tied to anything after your purchase.
Can Stuvia be trusted?
4.6 stars on Google & Trustpilot (+1000 reviews)
75759 documents were sold in the last 30 days
Founded in 2010, the go-to place to buy study notes for 14 years now