Molecular Pathology of Tumours Flashcards
What is the multi step process that leads to metastasis?
Normal
I
V
Dysplasia - some loss of stratification - immature cells escape from basal layer
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V
Carcinoma in situ - total loss of stratification, immature cells throughout basement membrane are intact
I
V
Invasion - Erosion of basement membrane, tumour gains access to vascular channels
I
V
(Cells escape from tumour via lymphatics etc)
I
V
Metastasis - secondary tumour (in lymph node etc)
If tumour cells have a clonal origin, how do different kinds of tumour cell (nonantigenic, invasive, etc) exist in the same tumour?
Some cell lines of the clone will have variants, which will form their own cell lines
What happens in oncogene activation and tumour suppressor gene inactivation?
Neoplasia
What are oncogenes?
- Drivers of neoplastic behaviour
* Proto-oncogenes undergo a single mutation event to create oncogenes
What kind of genes/genetic events have the potential to become oncogenic?
Coding sequences
Gene amplification
Chromosome rearrangement
What can oncogenes do?
- Growth factor – sis, fibrosarcoma
- Growth factor receptor - HER2, breast cancer
- Signal transducer – ras, colon cancer
- Transcription factor - myc, Burkitt’s lymphoma
How do oncogenes work?
A Direct stimulation of cell cycle dependent transcription
B Increased/activation of growth factor receptors
C Increased growth factor
D Interference with intracellular signalling
What is a dominant mutation?
A mutation that causes a gain of function
What is a recessive mutation?
A mutation that causes loss of function
How are tumour suppressor genes inactivated?
Both copies of the tumour suppressor genes have to be mutated in two separate events on each chromosome
What hypothesis posits to explain the cause of retinoblastoma?
Knudson’s two hit hypothesis
Why does mutating Rb drive carcinogenesis?
Inactive Rb does not end to E2F on the DNA thus activating the protein. This will then cause the activation of the expression of the S-phase of the cell cycle
What do gatekeepers do?
- Inhibit proliferation or promote the death of cells, especially those with DNA damage
- Send negative signals to the cell
What do caretakers do?
- Maintain integrity of the genome by promoting DNA repair
- Nucleotide excision repair
- Mismatch repair
- DNA double strand break repair
Name a gatekeeper
p53
What does gatekeeper p53 do to a cell that has been mutated?
If active, it will repair the mutation or cause apoptotic cell death
How often is p53 mutated?
p53 is frequently mutated in a wide range of different tumours
Most notably cancers of the ovary and oesophagus
What does p53 do in the face of a lack of nucleotides, UV radiation, ionising radiation, oncogene signalling, hypoxia or blockage of transcription?
Cell cycle arrest leading to senescence or return to proliferation
DNA repair
Block of angiogenesis
Apoptosis
What impact does a variation of the rate of apoptosis have on homeostasis and what does it balance?
Normal cell division and decreased apoptosis creates a tumour just as increased cell division and normal apoptosis does.
What tumours are BCL-2 linked to?
Follicular lymphoma - Leads to overproduction of antibodies
What limits ability to replicate?
The generational reduction in telomeric DNA
What does introduction of telomerase to cells in culture do?
Immortalise them - ‘Immortal life of Henrietta Lacks’
What is the angiogenesis signalling cascade?
Cancer cell releases VEGF (or bFGF)
This binds to receptor protein on endothelial cell surface
It is then passed through relay proteins to nucleus
Genes are activated in cell nucleus
Proteins stimulate new endothelial cell growth
How can one recognise a blood network affected by tumours?
It has no, or only residual, structure found in the arterioles -> capillaries -> venules of a normal mature network
Is just a big mess inappropriate to location
How do tumour cells in the bloodstream/lymphatics form a metastasis?
Cells released into the bloodstream will travel to a site where they will adhere to the vessel wall
Only 1 in 1000 will survive to form metastasis
They will then escape from the blood vessel and enter whatever structure the vessel supplies to form a micrometastasis
They will then proliferate and colonise to form a full blown metastasis
How do tumour cells penetrate the basal lamina?
A. Loosening of intercellular junctions
- Tumor cells detach from each other because of reduced adhesiveness
B. Attachment
- Cells then attach to the basement membrane via the laminin receptors
C. Degradation
- Cells secrete proteolytic enzymes, including type IV collagenase and plasminogen activator
D. Migration
- Degradation of the basement membrane and tumor cell migration follow.
What are the ‘7 deadly sins’ of tumour growth?
•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
