Molecular Pathology of Tumours Flashcards
What genes are altered in genetic mutations that result in cancers
Oncogene activation and tumour suppressor inactivation
What are oncogenes?
Drivers of neoplastic behaviour (ability to grow without reference to normal control mechanisms)
How are oncogenes derived from proto-oncogenes?
By a single mutation event, it activated the pronto-oncogenes into an oncogene.
What the single mutation events that lead to oncogenes?
A single mutation in coding sequence, gene amplification or chromosomal rearrangement. These lead to sustained protein activity or an increase in protein activity
How do oncogenes work?
1) Directly stimulation of cell cycle dependant transcription.
2) Increased/activation of growth factor receptors.
3) Increased growth factor
4) Interference with intracellular signalling
How are tumour suppressor genes eliminated?
First mutation event inactivates the tumour suppressor gene (TSG) on one chromosome. A second mutation event inactivates the TSG on the second chromosome leading too elimination of TSG, stimulating cell survival and proliferation.
What is the overall, general function of tumour suppressor genes?
They tell the cell not to divide so they suppress cell division
In retinoblastoma what is the difference between early onset bilateral retinoblastoma and later onset unilateral retinoblastoma
In bilateral - They tend to have an inherited mutation in the Rb gene so they only have one working copy in every cell, therefore a mutation only needs to occur in the one chromosome for the individual to be affected.
Why does a mutated retinoblastoma drive carcinogenesis?
A mutated Rb remains inactive due to the inactivating mutation so the cell is sent towards uncontrolled proliferation. (active Rb inhibits synthesis of genes required for DNA synthesis)
What is the function of gatekeeper tumour suppressor? genes?
Inhibit proliferation or promote the death of cells, especially those with DNA damage. Sends -ve signals to cells.
What is the function of caretaker tumour suppressor genes?
Maintain integrity of the genome by promoting DNA repair via; nucleotide excision repair, mismatch repair or DNA double strand break repair.
How does the tumour suppressor gene p53 act?
As both a gatekeeper and caretaker. It can induce apoptosis, DNA repair, block of angiogenesis or cell cycle arrest.
What is the nature of p53 mutations and where are they commonly seen?
They tend to be missense mutations are are seen in a WIDE variety if tumours.
What are the ways cells can increase in number in tumour formation?
Via increased cell division or decreased apoptosis.
What is the role of Bcl2?
It prevents cell death so increased Bcl2 expression can lead to tumour formation
What occurs in the absence of telomerase?
The cell goes into crisis because when telomerase is absent the genetic material becomes shortened. The function of the telomere is to protect the central information of the chromosome.
What is the role of telomerase in tumours.
Telomerase can immortalise cells, therefore tumours which have active telomerase in them decrease the survival rate.
What is VEGF?
A growth factor which stimulates cell growth and angiogenesis
What occurs when cells become deoxygenated?
They produce VEGF which stimulates the sprouting of new vessels from existing ones (angiogenesis)
Describe the blood vessels produced by tumour cells?
They are unstable with abnormal function and structure and increased permeability.
Describe the process of invasion of tumour cells
Tumour cells detach from each other due to reduced adhesiveness. Cells then attach to BM via laminin receptors. Cells secrete proteolytic enzymes (type IV collagenase and plasminogen activatior). Degradation of the basement membrane and tumour cell migration follows.
