Samenvatting
Samenvatting Oncology
- Instelling
- Vrije Universiteit Amsterdam (VU)
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[Meer zien]Voorbeeld 4 van de 52 pagina's
Voorbeeld 4 van de 52 pagina's
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Voorbeeld van de inhoud
NATURE OF CANCERClinical definitions of cancer
The incidence of cancer is defined to be the number of new cases that is registered within a certain
period (mostly 1 year). To be able to follow the incidence in time, or to enable comparison between
regions, the incidence is mostly expressed as the number of new cases per 100.000 inhabitants/persons
each year: the crude incidence rate. The prevalence of cancer comprises all persons who somewhere in
time have been diagnosed with cancer and are still living at a certain date. Hence, this is a diverse group,
ranging from persons who have been cured from cancer in the past to persons who just have been
diagnosed with cancer. The period can be unlimited, but also defined. As an example: the 5-year
prevalence on January 1st, 2020, comprises all still living people who have been diagnosed with cancer
since January 1st, 2015. The mortality of cancer comprises the number of patients who died because of
cancer within a certain period (mostly 1 year). Survival is the percentage of patients still living at a certain
period after diagnosis. The presented survival is a relative survival that approaches the “cancer-specific
survival.” This means that the survival observed is corrected for the expected death within a comparable
population (with respect to country/region, gender, age and calendar year).
Cancer is a group of diseases. More than 100 cancer types can be distinguished (or even every tumour is
different). All cancers are characterized by uncontrolled cell growth, is invasive and forms metastases. A
tumour is a mass of cells, but not every tumour is invasive and metastasising. So, benign tumours are no
cancer, only malignant tumours are cancer. A malignant tumour is life threatening because the invasion
of organs disturbs the organ function. The cancer cells compete with normal cells for nutrients and
oxygen. Growing tumours can also cause obstructions. There are different names for tumours:
Carcinomas arise from epithelia ( ̴85% of all cancers)
Adenocarcinomas arise from glandular tissues (e.g., breast)
Sarcomas arise from mesodermal tissues (e.g., bone, muscle)
Lymphomas arise from (progenitors of) white blood cells
The incidence of carcinomas is much higher because the epithelial cells align the body (inside and
outside) and are therefore most exposed to carcinogens. A carcinogen is an agent causing cancer
(compound, radiation, etc.). It causes alterations in the DNA of a cell. The accumulation of mutations in
the DNA of a cell causes stepwise development of cancer (oncogenesis). This development goes as
follows: normal epithelium, hyperplasia, dysplasia, carcinoma in situ, invasive carcinoma and metastases.
It all starts with a first mutation in a single cell. All tumour cells, in the end, are derived from this one cell,
which makes cancer clonal. After splitting, the cells proliferate and 1 cell
can develop an extra mutation, which results in different cells. They all carry
the same mutation that was in the original cell, but along the way, they
acquire mutations, which results in a heterogenous mass of cells.
Almost all the mutations develop in somatic cells and will not be passed to the next generation of
offspring. This makes cancer not inheritable. However, some inherited germline mutations can increase
the chance to develop cancer and these can be passed on to the next generation of offspring. These
mutations are rarely involved in causing cancer immediately.
There is a higher risk to develop cancer at an older age, because an accumulation of mutations in the
DNA is needed for the development of cancer. It is a matter of chance and time (exposure to
carcinogens). The incidence of cancer is increasing due to a longer life expectancy.
Main characteristics of cancer
,There are the main characteristics of cancer, which are 10 hallmarks. A tumour
is more than just tumour cells. Tumours are heterogenous, but they also
contain non-malignant cells from the body in which the tumour is growing.
There are fibroblasts (connective tissue), but also blood vessels and immune
cells present. The growth of a tumour is caused by a disturbed balance
between proliferation, cell death and differentiation. There is an increased stimulation of proliferation
and a loss of cell death and differentiation.
It is possible to recognize cancer cells in tissue cultures because cancer cells have a different morphology,
they can grow at low serum concentrations, they show no/decreased contact inhibition and they can
grow without substrate for attachment. The factors that play a role in the development of cancer are:
Environment (soot, sunlight, asbestos)
Diet (fruit and vegetables, fish) and exercise
Alcohol (head and neck, breast)
Smoking (>80 carcinogens; 40% of all cancer deaths)
Reproduction, contraception, hormone replacement therapy
Viruses (sexual transmittable)
Own metabolism (by-products of metabolism and errors in DNA replication)
Treatment of cancer
The conventional modalities of cancer treatment are surgery, radiotherapy,
chemotherapy, prevention of cell division (cytostatic effect) and killing of
cancer cells (cytotoxic effect). However, these
treatments exert adverse events/toxicity on normal
tissues. Also, the therapeutic index/window of most
chemotherapeutics is relatively small. The therapeutic window is the difference
between the maximum tolerated dose (MTD) and the minimum dose needed to
exert anti-cancer activity. The therapeutic index is the difference between the
tumour response and the normal tissue toxicity at 50% effect. The aim of cancer
treatment is to develop novel anti-cancer agents with selective activity against cancer cells, thus causing
less toxicity, which are targeted drugs. Every ‘hallmark’ is a potential target for this selective therapy.
Only a small proportion of patients benefits from the treatment with the current drugs, because tumours
differ from each other. Therefore, different patients need different treatments. So, there needs to be
defined which patients will benefit and which will not. This is done with diagnostics, such as genetics,
imaging and immunohistochemistry.
DNA STRUCTURE AND
STABILITY
DNA structure and integrity
Every cell has a DNA length of 2 meters, which must fit into a nucleus of 6 μm. For this,
the DNA is wrapped around protein complexes, which are histones. The DNA is wrapped
around the histone twice and this is called a nucleosome. 2 sister chromatids together
form a chromosome. These 2 are kept together at the centromere. Here, large protein complexes are
being assembled, called kinetochores. These make up the connection between the chromosome and the
mitotic spindle, which pulls the sister chromatids apart to make them end up in different
daughter cells.
The backbone of the DNA-strand is made up from sugar and phosphate. The 3’- and 5’-
end are established by counting the water atoms of the sugar (top one is an oxygen atom). Each sugar is
,connected to a specific base. This can be a pyrimidine or a purine. Thymine and cytosine are pyrimidines
and adenosine and guanine are purines. The cytosines bind to the guanines by making 3 hydrogen bonds
and the adenosine binds to the thymine by making 2 hydrogen bonds. The sequence of the bases is
crucial for the function of the DNA.
The transcription of DNA starts at the transcription start site, which transcribes the DNA into RNA until
the transcription stop site. This piece of RNA is further spliced into mature mRNA. Splicing means that
the intron sequences are removed. The finished transcription product contains only exons. The mature
mRNA can be translated into proteins, which consist of amino acids. Whereas DNA only has 4 bases,
amino acids come in 20 variants. To make 20 amino acids from only 4 bases, the cell uses codons, which
are triplets of 3 consequtive DNA bases that encode 1 amino acid.
Upstream of the transcription start site (5’-end), there is an important piece of DNA, called the promotor
sequence. This sequence contains response elements that are bound by specific proteins, which are
transcription factors. These regulate the expression of the gene. In addition, there are other regulatory
elements that can be further away or in intronic sequences, which also help regulating whether a gene is
expressed.
Types of DNA aberrations
There are small DNA changes that can influence the protein that is made during
translation. These changes are base pair substitution, insertion and deletion. A base pair
substitution causes an amino acid change (which can also be a stop
codon) and insertion and deletion cause a possible frame shift and can also result in a
premature stop codon. There are also large DNA changes possible. These include
aneuploidy, gene amplifications, deletions and chromosome rearrangements.
Aneuploidy is the loss or gain of a whole chromosome. Gene amplifications can happen intra-
chromosomal (piece of DNA is copied multiple times in 1 chromosome) or extra-chromosomal (DNA will
be present in cell outside of chromsome, don’t contain centromere, so no equal distribution over
daughter cells). Deletions can be small (1 basepair), but also large (multiple genes at once).
Translocations are an example of chromosome rearrangements. All these changes in DNA can lead to
genetic instability. If there is DNA damage and it is not repaired, the changes are permenant leading to
DNA mutations, amplifications or deletions. Eventually, this can lead to changes in cell function, which
can be the starting point of cancer. So, cancer can result from (epi)genetic alterations in human cancer
genes:
Stability genes (e.g. repair) Inactivation
Oncogenes (e.g. growth factors) Activation
Tumor suppressor genes (e.g. TP53) Inactivation
Carcinogenesis is a multi-step process. It is often initiated by DNA mutations (more than 1), leading to
damage of the DNA:
1. Initiation
DNA damage, chromosomal
damage, > 1 mutation
2. Promotion
Cell proliferation, influenced
by intercellular processes,
growth factors, hormones
and environmental factors
3. Progression
Invasion, migration, metastasis, angiogenesis
Causes of DNA aberrations
There are multiple sources that can affect the DNA, including endogenous and exogenous sources. The
exogenous sources are smoking, alcohol, sunlight (UV) and radiation. The endogenous sources are DNA
replication errors and reactive oxygen species (ROS), which are produced during the oxidative
phosphorylation in the mitochondria.
, Radiation is energy, which is usually in
waves, but there is also radiation by
particles. X-ray and gamma ray are
considered ionizing radiation. They
have high frequency electromagnetic
radiation. If energy (in the form of
radiation) hits an atom, it can happen
that an electron is being emitted,
which is the ionization of the atom.
This results in a positive atom and a
negative electron, which are both very
reactive. The electron can damage the
DNA of cells either directly or indirectly via the production of ROS. This indirect damage can be caused by
the radiolysis of water. The ionization of a water molecule causes the emission of an electron and a
cascade of subsequent reactions. The hydrogen atom of a nearby water molecule will be stolen, which
results in H3O+ and OH-. OH- is a very reactive molecule, because it searches for an electron to pair with.
The electron freed by radiation can be stabilized by multiple water molecules, but it can also pair with
another water molecule, which leads to the removel of an hydrogen and results in an OH-. The ROS that
form can react with DNA. This can happen directly and indirectly. The indirect action is through radiolysis
of water, which will result in ROS that can chemically react with DNA. A R* will detach from the DNA (* =
free radical). This unstable molecule will either be reduced by an SH-group or react with oxygen, making
the DNA lesion permanent. The electron freed by radiation can also directly affect the DNA (30%).
Antioxidants can inactivate ROS species (glutathion, vitamines A, C and E). For example, guanine can be
turned into 8-oxoguanine (addition of oxygen molecule) by ionizing radiation or normal cellular
metabolism (aging). This is potentially mutagenic because DNA polymerase reads it as thymine.
The amount of damage by radiation depends on the rate at which energy is released. This is measured
with the linear energy transfer (LET), which is the rate of energy loss along the track of ionizing particle:
Low LET X-rays, gamma rays, proton
High LET α-particles, neutrons, carbon-ions
The amount of energy deposit is measured in Gray (Gy), with 1 Gy = 1 joule/kg tissue. The amount of
biological damage caused by radiation is measured in Sievert (Sv), it is the absorbed dose in Gy
multiplied by the radiation quality factor (= 1 for photons, 20 for neurons).
Diffuse ionization track Dense ionization track
The higher the LET of radiation, the higher the energy deposit over short distance. There is more cell kill
per Gy and also lower penetration dept in material/tissue (α-particles are stopped by a sheet of paper,
while gamma rays are stopped by a few inches of lead).
Factors determining carcinogenic risk of radiation:
Exposed volume
Total dose, dose rate and dose per fraction (no threshold dose)
Organ / tissue specific sensitivity for cancer induction (leukemia most frequent ionizing radiation-
induced cancer, risk of solid cancer increases with dose in linear fashion)
Host susceptibility (genetic predisposition, immunodeficiency)
Biological factors (e.g. hormonal status, tissue repopulation rate)
Shape of the dose-cancer risk incidence curve: organ specific
Gender
Age at exposure (children are most sensitive to radiation)
Environmental factors
Other biological / physical factors
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