Molecular Pathology of Tumours Flashcards
What is a property unique to a malignant cell ?
Ability to spread to other parts of the body.
State some properties of malignant cells
Disordered:
- Proliferation
- Apoptosis
- Differentiation
- Relationship between proliferating cells and surrounding environment
(invasion, metastasis, angiogenesis)
Describe the multi-step process of tumour formation
Normal
Dysplasia
Carcinoma in situ
Invasion (basement membrane is broken)
Metastases
Describe tumour formation - clonality
A mutation gives one cell an advantage
A second mutation increases the advantage.
A third mutation increases the advantage further and makes the cell invasive.
Dangerous cell survival, proliferation and invasion.
What sort of genes are altered in mutations ?
Oncogene activation
Tumour supressor gene inactivation
What are oncogenes ?
- Drivers of neoplastic behaviour (out of control proliferation)
- Proto-oncogene
How are oncogenes formed ?
A single mutation event in a proto-oncogene creates an oncogene.
The activation of the mutation, enables the oncogene to stimulate cell survival and proliferation.
What type of mutation occurs for proto-oncogenes ?
DOMINANT mutation
Activating mutation
Gain of function (excessive cell survival and proliferation)
Give an example of an oncogene
RAS
What mechanisms can result in the activation of an oncogene ?
Mutation in the coding sequence
Gene amplification
Chromosome Re-arrangement
Describe a mutation in the coding sequence - RAS
Can happen in an oncogene like RAS.
Found in colon cancer, where the 12th amino acid of RAS is converted from glycine to valine.
RAS protein becomes locked in an ON position, and is able to send signals down the cascade to tell cells to divide.
Result of a mutation in the coding sequence
Hyperactive protein made in normal amounts
Describe gene amplification : HER2
HER2- epidermal growth factor
Frequently happens in breast cancer.
Amplification of HER2 gene, which over expresses the protein to a high extent.
Result of gene amplification
Normal protein greatly overproduced
Describe chromosome rearrangement : CML (chronic myeloid leukaemia)
Rearrangement of Philadelphia chromosome, in order to generate a fusion protein.
BCL gene fused to abl gene.
This produces a hyperactive fusion protein.
Result of chromosome re-arrangement
Fusion to actively transcribed gene produces hyperactive fusion protein.
OR
Nearby regulatory DNA sequence causes normal protein to be overproduced.
Functional consequences of oncogenes
What are there mutations in ?
Mutations in:
- Growth factor
- Growth factor receptor
- Signal transducer
- Transcription factor
Growth factor mutations
Sis (over expressed gene), Fibrosarcoma
Growth factor receptor mutations
HER2, Breast cancer
SIgnal transducer mutations
Ras, Colon cancer
Transcription factor mutation
Myc, Burkitt’s lymphoma
How do oncogenes work ?
Four ways
4 ways:
Direct stimulation of cell cycle dependent transcription.
Increased/activation of growth factor receptors
Increased growth factor
Interference with intracellular signalling
Describe tumour suppressor genes
Recessive mutation
LOSS of function mutation
Excessive cell survival and proliferation
Feature of tumour suppressor genes
LOSS of function mutations (2 inactivating mutations) functionally eliminates the tumour suppressor gene, stimulating cell survival and proliferation.
Retinoblastoma: Knudson’s 2 hit hypothesis
Normally paired RB1 genes
Mutational loss of one RB1 gene
Mutational loss of the other RB1 gene in the same cell/ its daughter cell.
This may lead to 1 eye with retinoblastoma. Other eye with none of these cells - normal.
Inherited absence of 1 of the paired RB1 genes.
Mutational loss of RB1 in any retinal cell
High risk of bilateral retinoblastoma
Bilateral retinoblastoma
Inherited retinoblastoma
Only need 1 mutation
Earlier age of onset
Unilateral retinoblastoma
Sporadic retinoblastoma
Needs 2 mutations to occur
Normal function of RB1
A transcription factor, which sits on top of other transcription factors and prevents the expression of genes, which are required for DNA synthesis.
Why does mutating RB drive carcinogenesis ?
Non-proliferating cell.
Inactive Rb, in an uncontrolled way (mutated).
We can activate transcription and expression of S-phase genes are activated.
State the 2 types of tumour suppressor genes
Gatekeepers
Caretakers
Gatekeeper - tumour suppressor genes
Inhibit proliferation or promote the death of cells, especially those with DNA damage.
Sends negative signals to the cell.
Example of a tumour suppressor gene mutation - gatekeeper
Familial adenomatous polyposis coli
Retinoblastoma
Describe caretaker - tumour supressor genes
Maintain the integrity of the genome by promoting DNA repair.
- Nucleotide expansion repair
- Mismatch repair
- DNA double strand break repair
Examples of tumour suppressor gene mutations - caretaker type
Xeroderma Pigmentosa
Hereditary non-polyposis colon cancer
Breast & Ovarian Cancer
State a tumour suppressor genes that is both a caretaker and a gatekeeper
p53
p53 is widely mutated in a wide range of different tumours
p53
tumour suppressor gene
Li-Fraumeni family
Inherited mutation in p53
Predisposes them to a wide variety of cancers.
What is a missense mutation ?
Amino acid substitution
Result of a mutation in the p53 gene
Loss of function
(normal function is tumour suppressor)
Nature of p53 mutations
Sequence specific DNA binding
What does p53 do ?
Four things
Stimulates:
- Cell cycle arrest
- DNA repair
- Block of angiogenesis
- Apoptosis
What activates p53 ?
Cell damage
- UV radiation
- Lack of nucleotides
- Hypoxia
- Blockage of transcription
Describe homeostatic / normal situations
Normal cell division
Normal apoptosis
Describe tumour formation situations
IN some either:
- Increased cell division / normal apoptosis
- Normal cell division / decreased apoptosis
BCL2
Anti-apoptotic
Inhibits cell death pathway
Importance of BCL2
IN some instances, the genetics around BCL2 can be re-arranged as part of chromosome translocation.
The wrong promotor can end up in front of BCL2, meaning BCL2 is over expressed.
This results in lymphoma.
(increased cell survival, decreased cell death)
Key feature of tumour
Limitless replicative potential
Telomerase can be active is tumours - associated with the worst prognosis
Multi-Step model of carcinogenesis
Normal epithelium
(tumour supressor gene (APC) lost)
Excessive epithelial proliferation
(Oncogene (Ras) activated)
Small tumour
(Another tumour suppressor gene lost)
Large tumour
(A 3rd tumour supressor gene (p53) lost)
Tumour becomes invasive
(rapid accumulation of mutations)
Metastasis
How can DNA be damaged ?
Chemicals
Radiation
Viruses
Describe a chromosome
Ends of the chromosome (telomeric DNA)
Body of chromosomal DNA
ENDS - repeated many times to protect the ends of the chromosome and make sure it always remains a standard length.
Angiogenesis Signalling Cascade
Cancer cell
VEGF - vascular endothelial growth factor
This factor sends a signal to endothelial cells stimulating growth of new blood vessels.
Telomerase function
Recognises the telomeric DNA and maintains it at ideal lengths.
When is telomerase expressed ?
Telomerase is highly expressed in dividing cells.
In differentiated, somatic cells, telomerase is no longer expressed.
So as cells undergo successive divisions, there becomes a crisis point where telomere DNA is so short that the chromosome becomes unstable.
Endothelial cell activation
Activated endothelial cells
Secretes MMPs that digest surrounding matrix
Cell migrates and divides
How do tumour cells go from being in a benign state to metastatic state ?
Cells grow as a being tumour in the epithelium.
Cells become invasive, break through basement membrane and enter the capillary.
They adhere to the blood vessel wall.
Escape from the blood vessel to find a new home.
Colonise that new home.
Changes that occur leading to metastases
Tumour cells detach from each other because of reduced adhesiveness.
Cells then attach to the basement membrane via the laminin receptors.
Cells secrete proteolytic enzymes, including type IV collegenase and plasminogen activator.
Degradation of the basement membrane and tumour cell migration follow.
Easy stage of invasion and metastasis
Travel through circulation
Difficult stages of invasion and metastases
Escape from parent tissue
Colonisation of remote site
‘7 deadly sins’ of tumour cells
Self-sufficiency in growth signals
Insensitivity to growth-inhibitory signals
Evasion of apoptosis
Defects in DNA repair
Limitless replicative potential
Sustained angiogenesis
Ability to invade and metastasise.