Samenvatting
Samenvatting Mechanisms Of Disease 2
- Instelling
- Universiteit Leiden (UL)
Samenvatting op basis van alle leerdoelen
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Voorbeeld 4 van de 86 pagina's
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Voorbeeld van de inhoud
Samenvatting MOD2 door Lieke Touwen. Alleen voor individueel gebruik.Leerdoelen MD2
Theme I: Neoplastic disorders: introduction to cancer (A + B)
Denominates the processes that initiate and influence tumor development and relates these to
phenotypical characteristics of tumor cells.
Cancer can occur in different tissue in the body. It all starts in a normal functional human cell that
develops to a cancerous cell. It is a progressive development from normal to neoplastic tissue with
many non-malignant intermediate stages. It starts with a mutation in a cell. This is the
initiating mutation that does first clonal expansion, leading to many more cells with
the same mutation. It has growth advantage over the other cells, making it easier to
replicate. The second, third and fourth mutation occur, all leading to more clonal
expansion. Thus, cancer development is driven by the accumulation of mutations.
A mutation is a permanent alteration in a parental DNA sequence. It can be on cell level, so in a part
of the body, or in an organism. The somatic mutation in the cell gives it to its daughter cells, while
the mutation in the whole organism is also present in the germline. This means that the mutation is
hereditary and given to the offspring.
There are different classes and types of mutations. There is chromosome mutation that may effect
the expression of many genes, or gene mutations that may affect the expression of a few genes.
Examples of chromosome mutations are chromosome losses/gains,
translocations or multi-locus deletions.
Multi-locus deletions are the deletions of many genes in the
autosomal chromosome. This leads to loss of function of the deleted alleles. The deleted genes are
not functional anymore and only the genes on the other allele can be expressed. This makes the cell
hemizygosity for multiple genes, meaning that only one allele remains.
Intragenic deletions are the lost of exons on the DNA strand. Most of the time there is loss
of function, but this is not always the case. The mutagenic consequences can vary. If an
exon is deleted, but there is no change in the reading frame, the gene and protein is still
expressed, but often smaller. This could still be (partially) functional. If an exon is deleted
and there is change in the reading frame for example an early stop codon, a truncated protein is
produced that is most likely not functional at all.
Examples of gene mutations are deletions/insertions, base pair substitutions or frameshifts. An
intron is most often not affected. The promotor may affect transcription efficiency when mutated
but has mostly no effect. Exon loss of gain may affect protein composition by changing in the reading
frame. Splice site may affect splicing, for example causing exon skipping. An exon or intron always
begins with the GT and ends with AG. Splicing does not result in the formation of mutation.
The mutagenic consequences of the mutations can be frameshift, nonsense mutation or missense
mutation. Frameshift is the deletion of one nucleotide. This leads to a different reading frame, often
with an earlier stop codon. This leads to protein truncation with (partial) loss of function. Nonsense
mutation is the change of one nucleotide, so the whole base pair changes. The change leads to a stop
codon leading to protein truncation and (partial) loss of function. Missense mutation is a non-
synonymous amino acid change, so the nucleotide changes leading to a different base pair. There is a
difference in charge locally, so it is hard to predict if there will be (partial) loss of function, since it can
still be a functional protein. It depends on where the mutation occurs in the DNA strand. If it occurs in
the evolutionary conserved regions (ECR), impaired function or loss of function will probably occur.
These regions are formed over evolution and maintain the same
sequence with a lot of selective pressure to keep their function.
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Mutations need to occur to cause cancer. 6-7 mutations are needed to convert a normal epithelial
cell into an invasive carcinoma. The mutation rate for a gene in somatic cells 1 in 10 million. The
mutation frequency is very low. However, during every cell division can mutations occur and there is
probably 10^16 cells turn over during human life. Cancer still exist. Some mutations will cause
genomic instability leading to an increase mutation rate. The mutation rate for some types of
mutations is much higher than 1 in 10 million. There are also other mechanisms that
can cause impair gene function, for example epigenetic silence of genes. The last
reason is that some people carry predisposing mutations.
There is a lot of difference between a normal cell and a cancerous cell. This is
characterized in the hallmarks of cancer. There are 8 fundamental changes in cell
physiology and 2 enabling characteristics.
The first one is sustaining proliferative signalling. Tumor cells want a continue process of
cell growth. They can inhibit or mutate different pathways/genes leading to this goal. They
can produce and secrete growth factors independently that bind on the growth factor
receptor and active the downstream pathways of cell growth. They can mutate the growth
factor receptor causing active receptors all the time. They can mutate intracellular signal
molecules like Ras. They can mutate the transcription factors leading for example to
amplification of MYC. Lastly, they can mutate the components of the cell cycle control
network like D cyclins. Important to remember is that only one allele needs to be mutated
since there can be spoken of a dominant phenotype. All tumors require mutations that will
sustain proliferative signalling.
The second hallmark is evading growth suppressors. Most body cells are not growing and
thus suppressed by growth suppressors. If they need to proliferate and grow, the growth
promotors are activated. There is an equilibrium between the growth promotors and the
growth suppressors. Before the S phase, so in G1 there is a restriction point. In tumor cells
the Rb protein is mutated by phosphorylation for inactivation of the restriction point. The
Rb gene has a major role in growth arrest. This leads to no control of the cell cycle control.
The mutation of the Rb protein is seen in more than 95% of all tumors. The mutation occurs
in the growth inhibitors like CDK p16 that leads to loss of function/inhibition. Growth
inducers/factors are mutated as well, like Cyclin D and CDK4. This result in
hyperphosphorylation of Rb driving growth control.
A lot of different integrity checkpoints are seen in the cell cycle. The checkpoints have
different functions, but they look for mutations and chromosome attachment and search
for damage DNA.
The p53 gene promotes apoptosis. It is active by hyperproliferative signals, DNA damage, telomere
shortening or hypoxia. If it is stable and active, it causes cell-cycle arrest, senescence or apoptosis.
Senescence is the stage where there is too much damage and as a result, the cell cannot proliferate
anymore. Mutations of this p53 gene occurs in more than 50% of all human tumors. The p53
protective pathways are affected in more than 90% of all tumors. Mutation leads to loss of the G1-S
checkpoint and reduced apoptosis/senescence. This causes proliferation of cells with DNA damage;
more mutation and chromosomal aberrations will occur and eventually genomic instability. The
hereditary heterozygous mutation in the TP53 gene is the Li Fraumeni syndrome. There is
development of multiple primary tumors of various kinds at young ages. It is dominant inheritance.
During replication and proliferation of cells in many tissues, the second ‘good’ allele will be lost.
Patients will always develop cancer. On the cell level it is a ‘recessive gene’, but since the good allele
will always be lost, it is dominant inheritance.
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Another pathway leading to proliferation is the Wnt signalling. Wnt binds to the WNT receptor
causing the break of the destruction complex of APC and beta-catenin. Beta catenin is degraded into
the nucleus leading to proliferation. Mutation of the APC leads to loss of the destruction complex
causing that beta-catenin is always found in the nucleus leading to proliferation. Individuals with a
germline APC mutation develop adenomatous polyposis coli cancer. At 40 years there is an almost
100% incidence. This is also dominant hereditary, but ‘recessive’ on cell level.
The third hallmark is avoiding immune destruction. Individuals with congenital immune-deficiencies
or immunosuppressive patients develop cancer at about 200 times the rate as immune-competent
individuals. The normal host cell displays multiple MHC associated self-antigens with the MHC class I
leading to a T cell response. Tumor cells that express different types of tumor antigens can lead to
four different outcomes: 1) the product of oncogene or mutated tumor suppressor gene cause an T
cell response with CD8. 2) mutated self-protein due to carcinogen, radiation or in melanomas cause
T cell activation. 3) overexpressed or aberrantly expressed self-protein cause T cell activation with
CD8. 4) oncogenic virus induces virus antigen specific CD8 activation. The tumor cells try to avoid the
activation of T cells. Immune evasion tumors happen due to failure to produce tumor antigen. This
can be due to antigen loss variant of the tumor cell leading to lack of T cell recognition of the tumor.
Another way is due to mutations in MHC genes or genes needed for antigen processing leading to
lack of T cell recognition of tumor. The last pathway is by production of immunosuppressive proteins
or expression of inhibitory cell surface proteins.
The fourth hallmark is enabling replicative immortality. Normal cell can only divide a maximal time
of 30 to 70 times. It depends on the species, age and the tissue. After that, they will enter a state of
senescence. They are still metabolically active but have lost their ability to re-enter the cell cycle. This
limitation is because of the concept of telomere shortening. The human telomeres contain 5-15 kb of
TTAGGG repeats. During every replication of the cell, the telomeres
shorten and eventually cell division will stop. Telomerase is required for
the replication of the telomeres. Somatic cells do not express this
enzyme. Tumor cells cause mutation of p53 activating the NHEJ
pathway. The cell comes in the bridge-fusion breakage cycle. If the
telomeres are too short for further replication, the chromosome will
break and starts sticking together with other chromosomes, causing
dicentric chromosomes. If telomerase reactivation occurs, the telomere
will increase in size and cancer occurs. If there is no reactivation, the cell will go into mitotic
catastrophe and die.
The fifth hallmark is tumor promoting inflammation. Infiltrating cells and resident stromal
cells will enable the cancer effects. They release factors that promote proliferation, remove
growth suppressors, enhance resistance to cell death, induce angiogenesis, activate invasion
and metastasis and evade immune destruction.
The sixth hallmark is activating invasion and metastasis. They acquire the capacity of
loosening up of tumor cell to tumor cell interaction by inactivation of E cadherin. They can
move to the basement membrane to enter the blood stream and proliferate in a new tissue due
to this. There is also degradation of the extracellular matrix due to expression of proteolytic
enzymes. The epithelial tumors undergo epithelial-mesenchymal transition. Important to
notice is that metastasis is an inefficient process since millions of tumor cells might be released
from a tumor per day but only a few are able to metastasize.
The seventh hallmark is inducing angiogenesis. Like normal tissues, tumors
require nutrients and oxygen as well as an ability to evacuate waste
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products. They start to have the capacity to induce angiogenesis when
they are more than 1-2 mm. Not all cancer types have this hallmark,
since leukaemia does not need this.
The eight hallmark is resisting cell death. Tumors cells want to avoid
apoptosis and start to inhibit the pathways of apoptosis. They can
interact with the pro-apoptotic factors like BAX/BAK causing no
upregulation. They can also increase the activation of anti-apoptotic factors like BCL-2, BCL-XL or
MCL-1. Mutation of apoptotic peptidase activating factor 1 leads to no activation of caspase 9.
Lastly, they can also upregulate the expression of inhibitors of apoptosis like IAP.
The nineth pathway is deregulation cellular energetics. Tumors cells start to reprogram the energy
metabolism. The normal differentiated tissue uses glucose to produce via the oxidative
phosphorylation 36 mol ATP. The proliferative tumor tissue uses glucose to make mostly lactate.
This is used as building blocks for new cells. The net energy production is also different since way
fewer ATP is produced (only 4 mol ATP). This is called the Warburg effect. Lactate stimulates
angiogenesis as well. Enhanced metabolism of glucose by tumors can be visualized by PET/CT scan
with the glucose analogMYCy FDG. After therapy waste products of FDG are still seen in the kidney
and bladder.
The tenth pathway is genome instability and mutation. Cell division requires accurate DNA
duplication. Th daughter cells inherit identical DNA from the maternal cell. The cell division is in ~5
hours, where 6 x 10^9 base pairs are copied almost flawlessly, so with less than 1 error per division.
Mutations can arise during the DNA replication. DNA polymerase makes around 60.000 errors per
cell division. The repair system is exonuclease with proofreading of the newly synthesized DNA.
There is reduction of misincorporation, so leading to around 600 errors per cell division. Germline
mutations affecting the proofreading domains of POL eta and POLD1
predispose to colorectal adenomas and carcinomas. Mutation in these
domains effect the working mechanism of proofreading. There is a
much higher probability to develop tumors.
The mismatch repair system leads to reduction of less than 1 error per cell division on undamaged
DNA. There is base misincorporation. It is capable to remove the newly synthesized strand so the
DNA polymerase can try again. An example of a mutation is Lynch syndrome.
Mutations can also occur due to replication of endogenously- and exogenously
induced DNA damaged. Treats to genome stability are lifestyle,
environmental/industrial, medial application and food source factors. Small base
alterations are bulky lesions, DNA breaks and crosslinks. UV light leads to a covalent
binding between two T nucleotides in the same strand. This leads to a replication
block. Replication cannot go further and stops at multiple sites, leading to cell death.
Translesion synthesis polymerases like Pol and REV1 can bypass the DNA damage,
so the replication is not blocked permanently. The polymerase might do it correctly, but it can also
lead to a mutation. Pol eta is the translesion synthesis polymerase used for UV light damage.
Translesion synthesis deficiency of Pol eta leads to XP. The patients are very sensitive to sunlight and
have a really high chance of developing skin cancer. Chemical instability leads to 10.000 lost of bases
per cell per day. The most common causes of spontaneous mutations are depurination or
deamination. Depurination means that a G is hydrolysed, leading to loss of the base. The sugar
domain remains, but there is no information during the replication, causing a mutation. Deamination
is the methylation of C at the 5’ end. This part in involved in controlling the transcription. Due to the
methylation, the availability of chromatine to transcription factors is changed. The deaminate C and
the T bases are closely related now and this will lead to G T pair and mutations. Important is to repair
the damage before the DNA is being replicated. Types of DNA damage repair pathways are base
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