Summary that includes all lectures given by Schuringa, Van Vught, Kruyt and de Jong.The topics of the lectures are: carcinogenesis, cancer stem cells, the role of oncogenes and tumor suppressor genes, the large variety of subtypes within hematological and solid tumors, the signaling pathways active...
Cancer mutation different mRNA different protein that has oncogenic/tumor suppressor
activity. It is a multistep process where, due to genetic changes, normal cells are transformed into
cancer cells with increasing rate.
- Benign always remains confined to its original location
- Malignant when tumour evades into its surrounding tissue they are termed malignant
Types of cancer – based on their origin
- Carcinoma – epithelial tissue
o Adenocarcinoma from the gland. Adenocarcinoma has a higher/abnormal density
of crypts, loss of normal crypt structure.
o Squamous cell carcinoma epithelium
o Most common cancers are from epithelial layers because there is a high turnover of
cells.
- Sarcoma from muscle tissue and connective tissue
o Osteosarcoma from the bones
o Liposarcoma from adipocytes
- Leukemia from hematopoietic cells
o Acute
o Chronic
o (non)-Hodgkin- lymphoma rare form of lymph node cancer
- Gliomas from brain cells
- Melanomas from pigment cells in the skin
Origin of cancer
- Inactivation of the same chromosome X results in origination of a monoclonal
cancer
o Glucose-6-phosphate dehydrogenase – involved in metabolism
o In normal persons – two copies
o In patient – one copy tumour must be monoclonal
- Only one of the two isoenzymes is active – either maternal or paternal
- Normal cells – sometimes paternal/sometimes maternal X chromosome is active
Two types of mutations result in cancer
1. Somatic mutations
- Derive from chromosomal translocations, radiation, viruses, smoking, obesity, diet, alcohol
etc. Epidemiology is important – environment has influence on prevalence of types of cancer.
External factors
o Radiation-induced DNA damage by UV light or radioactive agents
o Mutagens such as smoke, asbestos
, Viruses
o Human papillomavirus HPV
o Human immunodeficiency virus HIV – indirectly causes leukemia
The Ames test is used to analyse the mutagenicity of substance
They use rat liver extract – the liver detoxifies drugs and
sometimes results in an even more powerful drug. So
they use rat livers to see whether the drug is properly
metabolized by the liver or that it induces side effects.
Salmonella strain is incubated with either or without
histidine. When mutants grow, this indicates resistant
bacteria that can cause mutations , indicating that the
drugs are mutagenic.
- Not hereditary! Only hereditary when the mutation is in the
germline.
It was known for many years that viruses could cause cancer.
retroviruses can transform cells by inserting viral DNA genes oncogenes
proto-oncogenes they have a normal function but when disturbed, this can lead to cancer.
Most human and animals oncogenes are mutated forms of normal cellular genes (proto-
oncogene = normal state).
v-onc viral oncogene
c-onc cellular oncogene
- Premalignant lesion malignant lesion
Cervical cancer develops from less abnormal cells (premalignant cells)
From normal epithelium low-grade high-grade intra-epithelial neoplasm invasive carcinoma,
based on cervical cancer
Same is known for colon cancer normal epithelium polyp adenoma invasive polyp,
malignant.
- Multiple mutations lead to the emergence of cancer
, - The incidence of cancer increases with age, which indicates the accumulation of cancer-
causing mutations. Happens because of mutations frequency (1 mutation/gene/10 6 cell
divisions) – in case of the colon, this could happen very frequently.
- But mutations are needed for evolution, so they are also beneficial.
2. Germ mutations
- Genetic germ-line cells have mutations
- Mutation in germ-line cells occur in all cells, also all somatic cells. Patients that already
have one mutation in a tumour-suppressor gene, have a very high chance of getting cancer
(for example BRCA gene – breast cancer).
Cancer development is accelerated by (from benign to malignant)
Successive cycles of mutations
ultimately lead to cancer (cell
proliferation)
Mutations can be due to
a. gene inactivation
b. epigenetics: no protein expression
(silencing) due to
- histone modification
- DNA methylation
Not all mutations that arise due to epigenetics are vital – most lead to apoptosis of the cell. Only
when the mutations overcome certain ‘selection barriers’, they can lead to cancer.
- Cancer may arise from cancer stem cells: tumour initiating cells.
- Normal stem cells execute self-renewal. But some somatic cells get mutations/epigenetic
changes which gain the stem cell properties: which is continuously dividing.
chromosomal instability (translocations) and changes in total number of chromosomes
decreased cell death and differentiation
o loss of apoptotic ability
o apoptosis play an important role in embryogenesis and removal of old epithelial and
activated immune cells.
increased proliferation
o this is the case in colon cancer – polyp formation: increased proliferation in the
intestinal epithelium.
o more proliferated cells, but not less apoptotic cells
o disruption of homeostasis
normal 4 cells divide 8 cells.
For homeostasis, 4 cells needed in the end so 4 should go into apoptosis
The homeostasis is disrupted by either increased proliferation or decreased
apoptosis and thus contribute to tumorigenesis.
independence from environment (metastasizing)
o migrate through vessels
o vascular growth (angiogenesis) is required to supply the tumour – the tumour can
make its own vessels and thereby supplies itself.
, Identification of cancer-causing genes
oncogenes gain-of-function mutation
- dominant growth-stimulating effect
- mutation in only one allele is sufficient to get an activated pathway
- can be inherited – BUT offspring will be fatal because the genes have an important functions
and during embryogenesis there will be loss of function and the offspring wont survive.
- In their normal state they are proto-oncogenes, having an important function in cell division.
tumor-suppressor genes loss-of-function mutation
- hereditary cancer
- mutations in both alleles are required to get functional loss
So a mutation in an oncogene causes increased gene activity, whereas two mutations in tumour
suppressor genes are required to cause loss of gene activity. So cancer is caused by activation of
oncogenes or inactivation of tumour-suppressor genes.
There are three reasons for increased activity of a proto-oncogene
1. deletions or point mutations (Ras)
2. amplification and resulting overexpression (Myc)
3. chromosomal rearrangement (gene under control of another protein or fused with another
gene Bcr-Abl)
Examples of cancer-causing genes
Ras is an oncogene Ras/MapK pathway.
- Tumours target different pathways, because every cell has another pathway that dominates
Ras mutations always cause intracellular signalling – push the cell into a continued
proliferating state. Mutations in/overexpression of an oncogene (Ras) results in an increased
gene activity causing continuous proliferation and overcoming cell-cell contact inhibition.
Myc is an oncogene transcription factor
Gene amplification causes the normal gene to be overexpressed.
Bcr-Abl is an oncogene
Chromosomal translocation in chronic myeloid leukemia
(CML) leads to production of the Bcr-Abl fusion protein.
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