Oncogenic mutations sites in relevant proto and oncogenes
Leerstof Oncology Ch7/14
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Vrije Universiteit Amsterdam (VU)
Gezondheid en Leven: Klinische Wetenschappen
Oncology (AB_1184)
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H1: 21 blz → Irene = af
H2: 31 blz → Celeste
H3: 26 blz → Katja = af
H4: 30 blz → Lisa = af
H5: 20 blz → Tess
H6: 27 blz → Maud
,Chapter 1: Introduction
1.1 What is cancer?
Cancer is a group of diseases characterized by unregulated cell growth and the invasion and
spread of cells from the site of origin/primary site, to other sites of the body.
- Group of diseases → over 100 types of cancer have been classified; the
tissue of origin gives the distinguishing (onderscheidende) characteristics of the
cancer
o Carcinomas = cancer that occurs in epithelial cells = 85%
o Sarcomas = cancer that is derived from mesoderm cells (bone, muscle)
o Adenocarcinomas = cancer of glandular (klier) tissue (breasts)
The major factor that causes cancer in each target tissue is different, ultraviolet (UV)
radiation from the sun can easily target the skin, while inhalation of cigarette smoke can
target the lungs.
In addition, there are differences in the molecular mechanisms involved in carcinogenesis
within each cell type and the pattern of spread of cells from the primary site.
However, even though the underlying cellular and molecular routes may be different, the end
result is the same. Therefore, six hallmarks of cancer have been defined for most, if not all,
cancers. These six hallmarks are acquired for carcinogenesis. Recently two enabling
characteristics were included: genome instability and tumor-promoting inflammation. These
are crucial for acquiring the six hallmarks of cancer, and they highlight two emerging
(opkomende) hallmarks: reprogramming energy metabolism and avoiding immune
destruction à point for research.
1. Growth signal autonomy
+ Normal cells need external signals from growth factors to divide
+ Cancer cells are not dependent on normal growth factor signaling
→ Acquired mutations short-circuit (kortsluiten) growth factor pathways leading
to unregulated growth
2. Evasion (ontwijking) of growth inhibitory signals
+ Normal cells respond to inhibitory signals to maintain homeostasis (most cells of the
body are not actively dividing)
+ Cancer cells do not respond to growth inhibitory signals
→ Acquired mutations or gene silencing interfere with the inhibitory pathways
,3. Unlimited replicative potential
+ Normal cells have an autonomous counting device (toestel) to define (definieren) a
finite (eindig) number of cells doublings which they become senescent (verouderd). This
cellular counting device is shortening of chromosomal ends, telomeres, that occurs during
every round of DNA replication.
+ Cancer cells maintain (onderhouden) the length of their telomeres
→ Altered regulation of telomere maintenance results in unlimited replicative
potential
4. Invasion and metastasis
+ Normal cells maintain their location in the body and generally do not migrate
+ The movement of cancer cells to other parts of the body is the major cause of cancer
deaths
→ Alterations of the genome may affect the activity and/or levels of enzyme
involved in invasion or molecules involved in cell-cell or cellular-extracellular
adhesion (hechting).
5. Angiogenesis
+ Normal cells depend on blood vessels to supply oxygen and nutrients, but the vascular
architecture is more or less constant in the adult.
+ Cancer cells induce angiogenesis, the growth of new blood vessels, needed for tumor
survival and expansion (uitbreiding).
→ Altering the balance between angiogenic inducers and inhibitors can activate
the angiogenic switch
6. Evasion of cell death
+ Normal cells are removed by apoptosis, often in response to DNA damage
+ Cancer cells evade (ontduiken) apoptotic signals
7. Tumour-promoting inflammation (enabling characteristic)
- Virtually all tumours contain inflammatory immune cells
- Inflammation is an immune response that can facilitate the ability of acquiring the
core hallmarks of cancer inflammation kan het vergemakkelijken om aan de andere 6
hallmarks te voldoen. For example; inflammatory cells can provide growth factors and
enzymes that promote angiogenesis and invasion
- In addition (bovendien), inflammatory cells can release oxygen species
(zuurstofsoorten) that are mutagenic
8. Genome instability and mutation (enabling characteristic)
- Acquiring the core hallmarks of cancer usually depends on genomic alterations
- Faculty DNA repair pathways can contribute to genomic instability
9. Reprogramming energy metabolism (emerging hallmark)
- Uncontrolled cell division demands (eist) increases in fuel (brandstof) and
biosynthetic precursors that are obtained (verkregen) by adjusting (aanpassen) energy
metabolism.
, - Unlike normal cells, cancer cells carry out (uitvoeren) glycolysis, even in the presence
of oxygen. Glycolysis can be used in biosynthetic pathways.
10. Avoiding immune destruction (vernieOf zijntiging) (emerging hallmark)
- There is evidence to support the theory of immune surveillance that states the
immune system can recognize and eliminate cancer cells
- Successful cancer cells may be those that do not stimulate an immune response or
can interfere with the immune response so as to avoid immune destruction
Doordat de kankercellen een immuunrespons voorkomen, worden ze ook niet herkent en
geëlimineerd.
Cancer is characterized by unregulated cell growth and the invasion and spread of cells from
their site of the origin. This leads to the distinction between a benign tumor and a malignant
tumor.
· Benign (goedaardige) tumors do not metastasize, although some can be life-
threatening because of their location (brain tumor)
· Malignant (kwaadaardig) tumors do not remain encapsulated (ingekapseld), show
features (kenmerken) of invasion, and metastasize. They are life threatening because they
are physical obstructions, and, as they invade other organs, they compromise function. They
also compete fiercely (heftig) with healthy tissues for nutrients and oxygen.
Cancer cells can be distinguished from normal cells in cell culture conditions:
Normally cells grow as a single layer, known as a monolayer, in a Petri dish due to a
property called contact inhibition: contact with neighboring cells inhibits growth. Transformed
cells (cells that have become cancer cells) acquire the following phenotypes:
· They fail to exhibit contact inhibition and instead grow as piles (hopen) of cells or ‘foci’
against a monolayer of normal cells
· They can grow in conditions of low serum
· They adopt (aannemen) a ground morphology rather than a flat and extended one
· They are able to grow without attaching to a substrate (the surface or a Petri dish)
exhibiting ‘anchorage independence’
1.2 Evidence suggest that cancer is a disease of the genome at the cellular level
Most agents that cause cancer are agents that cause mutations in the DNA, cancer results
from alterations in DNA. The accumulation of mutations in cells over time represents a multi-
step process that underlies carcinogenesis. The requirement (eis) for accumulation of
mutations explains why there is an increased risk of cancer with age, and why there have
been more cases of cancer, because we are living longer. The longer we live, the more time
there is for our DNA to accumulate mutations which may lead to cancer.
→ There is evidence that in a small percentage of tumors, a single
catastrophic (rampzalig) event in a cell can lead immediately to many mutations
and cause cancer (chapter 2)
→ Only 5-10% of the mutations observed are thought to be directly involved
in causing cancer, based upon mathematical modeling
→ Almost all of the mutations identified in tumor cells are somatic mutations
whereby the DNA of a somatic (body) cell has been damaged. These mutations
can not be inherited, only germline mutations can be passed onto offspring.
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