What is a cancer initiating cell?
A normal cell type in which, or in whose daughter, cancer develops
What is a tumour initiating cell?
A cancer stem cell
Cancer cell which allows cancer to propergate around the body
What is the clonal evolutional model?
Cells divide and gain new mutations to become different cells
What is the hierarhcial/stem cell model?
Different types of cells in a tumour come from cancer stem cells
What was shown by the CFU-S by Bruce and Van der Gaag?
Only a subset of primary cancer tissue was able to proflierate in vivo; proving heterogenity of tumours and introducing the idea of cancer stem cells
Who first coined the idea of CSCs?
Hamburger and Salmon, 1977
Which hallmarks of cancer apply to CSCs and hence may be good therapeutic targets?
- Evasion of immune system
- Telomerase inhibitors (for some cancers)
- Induction of inflammation
- Ability to induce inavasion
- Ability to induce angiogenesis
- Resistance to cell death mechanisms
What are norman Maitlands hallmarks of CSCs?
- Isloated CSCs can cause tumour growth
- Isolated CSC are responsible for invasion and spread
- Isolated CSCs are present in minimal residual disease after convential treatment
- CSCs can differentiated from a more primitive phenotype to recognisable tumour phenotypes
- CSCs have a distinct phenotype to other cells in the tumour
What type of cell division is seen in stem cells?
Asymmetric cell division - one cell is different and one cell is a new stem cell for self-renewal
Why is assymetric division by stem cells important in cancer?
- Mutation is expressed in non-stem cell and may be killed by immune system or apoptosis etc.
- But in stem cell daughter it is hidden but still present
- When this daughter divides with a new muation this may be able to counteract apoptosis for example and allow the initial mutation to be effective
- Hence by hiding a mutation in the stem cell daughter untill the cell has acquired enough mutations to survive as a non-stem cell
Mutations in what type of mice cells can cuase cancer?
Normal colon stem cells but not amplifying cells
Barker et al
What are common malignaancy markers of CSCs?
- DNA Instability
- Resistance to radiation - 10X more resistant
What is different about proportions of cells in normal and tumour tissue?
In tumour tissue the stem cell poulation is very small in comparison to what is in normal tissue
What five common cancer treatments would not work for treating CSCs?
- Androgen abalation - CSC are AR-
- Radiotherapy - CSC are not rapidly dividing so not affected
- Chemotherapy - Express drug efflux transporters
- Gene therapy - Kills differentiated cells
- Immunotherapy - Kills differentiated cells
How does radiotherapy work?
Creates free radicals which cause damage
What does a COMET assay show?
If DNA is damaged then when ran on a gel will leave a tail behind it of pieces of broken DNA. Amount of DNA in the tail = amount of damage
What was shown about CSC by COMET assays?
CSC sustain less damage than amplifying or basal cells due radiotherapy or chemotherapy
What could be targeted for CSC therapies?
- Stem cell survival
- Stem cell differentiation
- Stem cell colony formation
How were cancer stem cell specific targets found?
What is being produced by cancer stem cells but not normal stem cells?
How does IL6 inhibition stop cancer?
Causes CSC to differntiated - and these differntiated cells cannot cause cancer alone