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Samenvatting Mechanisms of Disease
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- Universiteit Leiden (UL)
Samenvatting colleges mid-point exam (Theme 1A+1B)
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Voorbeeld van de inhoud
Mechanisms of Disease II Mid-point examTheme IA : Cancer biology and genetics.
Lecture 1 – Introduction :
Cancer is one of the most common and severe diseases affecting in some form or another
approximately one third of the population in the Western world and is responsible for about 20% of
all deaths. During this theme, we will discuss genetic alterations and cancer genes that have been
implicated in cancer etiology and development and additional cellular processes that accompany
malignant transformation. Special attention will be given to the cellular processes that govern
genome stability and protect the genome against DNA damage and mutations. You will learn both
the nomenclature of malignant tumors and the pathological and clinical differences between benign
and malignant tumors. The interaction between cancer cells and the patient’s immune system will be
studied and you will understand immune escape mechanisms adopted by tumors but also
therapeutic strategies that are aimed at boosting anti-tumor immunity. We will discuss how to
establish the diagnosis of cancer and its morphological and molecular characterization, including the
impact of recently developed technologies that allow the comprehensive screening of cancer
genomes in a diagnostic context. Also the hereditary aspects of some cancer types, like breast-,
ovarian-, and colorectal cancer will be discussed and how they are clinically managed in screening
programs.
Lecture 2 – Cancer biology :
The Hallmarks of cancer are 8 fundamental changes in cell physiology and two enabling
characteristics for a cancer cell to obtain. A cell does not have to have all the hallmarks to become
cancer.
The first hallmark is sustaining proliferative signalling. Normally a growth factor binds to a receptor,
leading to cell growth. Usually this is via Ras (= protein that is involved in intracellular communication
for cell growth). There are different types of mutations that will lead to cancer cells sustaining
proliferative signalling.
- First, there are tumor cells that start producing their own growth factors. They become
independent for their cell growth.
- Some cell surface receptors can mutate so that they become independent of the growth
factor.
- Intracellular signalling molecules could be mutated, causing it to be constantly active. Like
Ras in the previous lecture.
- Transcription factors like MYC could be mutated. This also leads to independent cell growth.
MYC is a DNA regulation gene that codes for transcription factors. These transcription factors
regulate the transcription of genes. A gene for a protein is more or less transcripted if that
protein is more or less needed. When mutated, a protein can always be produces because
the gene can always be transcripted.
- And lastly, components of the cell cycle control network like cyclin. Note that only one allele
has to be mutated, this is the dominant phenotype, because proto-oncogenes (growth) is
dominant. Cyclin is activated by growth factors, it then causes the hyperphosphorylation of
Rb, this cannot let go of E2F so E2F can bind to the genes and activates transcription.
,Mechanisms of Disease II Mid-point exam
The second hallmark is the evading growth suppressors (=
TSG). Normal cells can grow, but they are not always growing.
There is always a balance between growth suppressors and
growth promotors. There is a period during which cells are
responsive to EGF and PDGF (= kinds of growth factors) This is
during the G1 phase up until the R point. The phosphorylation
of Rb is required for the release of the restriction-point (= R
point), a point in the cell cycle after which no proliferative
signals are no longer needed (the entry ticket of transcription).
In 95% of all tumors, the Rb pathway is impaired. The loss of
function (due to mutation) of growth inhibitors like TGF-beta
and INK4a and the gain of function (due to mutation) of
growth factors like cyclin D and CDK4 are the most important
players to impair the Rb pathway. There are other checkpoints
in the cell cycle where mutations are checked, these are the
DNA integrity checkpoints. The G1 phase is the damaged DNA
checkpoint, phase S and G2 are the incompletely replicated
DNA checkpoints and the M-phase is the chromosome
improperly attached to mitotic spindle checkpoint. These checkpoints have a different function than
the R-point. These checkpoints are to prevent mutations. One key player in the mutation checkpoints
is the p53 protein. Factors like hyperproliferative signals, DNA damage, telomere shortening (factors
that show something is wrong) and hypoxia will lead to the stabilization and activation of p53. This
proteins then causes cell-cycle arrest, senescence (= ageing) or apoptosis to prevent the mutated cells
to reproduce. The P53 gene is mutated in more than 50% of all human tumors, mutations get passed
the guardian of the genome. P53
protective pathways are affected
in >90% of all tumors. Loss of p53
leads to loss of the G1-2
checkpoints and reduced
apoptosis. This leads to
proliferation of cells with DNA
damage causing mutation,
chromosomal aberrations,
ultimately leading to genomic
instability. A hereditary
heterogenous mutation in the
P53 gene is called Li Fraumeni syndrome. It develops multiple primary tumors of various kinds at
young age, it is dominant inheritance. Another important player in cell growth is the WNT receptor.
In a normal cell, the WNT receptor is not stimulated, that means that the protein APC is degrading
beta-catenin and that can therefore not stimulate proliferation. If the growth factor WNT binds, the
APC is no longer degrading beta-catenin and there is proliferation. In a tumor cell, the APC is
degraded (mutated) and the beta-catenin is not degraded anymore. There is proliferation,
independent of WNT growth factor. Individuals with a germline APC mutation have familial
adenomatous polyposis, they develop multiple (100-1000) polyps in the colon. These polyps can
become malignant and develop adenomatous polyposis colon cancer (at 40 years at an almost 100%
incidence).
, Mechanisms of Disease II Mid-point exam
The third hallmark is avoiding immune destruction. Individuals with congenital immune-deficiencies
develop cancer at about 200 times the rate as immune-competent individuals. Cancer rates are also
increased after immune-suppression like organ transplants and aids. Tumor cells are recognized by
the immune system because they have mutated
self-antigens, they have products of oncogenes or
mutated tumor suppressor genes. They are
recognized because they have overexpressed or
aberrantly expressed self-proteins or because they
have oncogenic viruses. In this case, immune cells
recognize tumor cells and clear them out. But
tumor cells can evade immune destruction. They
do that via different ways. First, the tumor cell can
lack antigens. This is an antigen-loss variant of the
tumor cell and there is a failure to produce the
tumor antigen. Secondly, the tumor cells are a
class I MHC-deficient tumor cell. Meaning that
there are mutations in MHC genes or genes
needed for antigen processing. The last way is a
production of immunosuppressive proteins or
expressing of inhibitory cell surface proteins. The
immune cells that do bind, will be suppressed or
inhibited to express that they have a tumor cell
bound.
The fourth hallmark of cancer is enabling replicative immortality. Normal cells have limited
proliferative capacity.
They can only multiplate a
limited number of times.
They enter a state of
replicative senescence (=
aging). At this state they
lose their ability to re-
enter the cell cycle but
they are still metabolically
active. The number of
doublings is dependent on
species, tissue and age of
the organism. Human
telomeres contain 5-15kb
of TTAGGG repeats. Telomerase is required for their replication. Somatic cells to not express the
telomerase. At every duplication, the telomere shortens and eventually is gone. At that moment the
cell division stops and the cell is then going into apoptosis. In cancer cells, the p53 is mutated,
meaning mutations can occur. P53 checks the telomeres and at a certain point of shortening tells the
cell to senescence. Without this, chromosomes replicate once more and can stick together, this is a
mutation called. This is called the bridge-fusion-breakage cycle. If this is multiplied, the chromosomes
will break. You cannot pull a chromosome with two chromatids or it will break. These broken
chromosomes will then start their telomerase reactivation. Meaning the telomerases will grow back
on. This is why cancer cells can then divide endlessly.
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