Lecture 5 - Cancer Stem Cells Flashcards
What are the 3 points on the triangle for cell devlopment?
Proliferation, differentiation and apoptosis
What 4 points challenge the hypothesis that cancer is a mutation of somatic cells?
- Most mature cells don’t proliferate
- Tumours are often heterogenous but cancers are clonal and arise from a single cell
- Most cells have a finite lifetime and don’t live long enough to acquire 3+ mutations
- Only a small number of tumour cells can recolonise why can’t all and what determines this?
What could be an answer to the conflicting hypothesis that cancer is a mutation of somatic cells
Cancer could derive from Cancer stem cells instead
What are embryonic stem cells?
- Pluripotent cells that can differentiate into many different cell types
What process can stem cells undergo most commonly and what is this?
Self renewal, reproduce themselves and generate more specialised cells indefinitely
What is an intermediate cell?
- precursors or progenitor cells which can develop into most but not all cell types
On a transcriptional and epigenetic level what examples of proteins regulate changes in cell fate?
Nanog, Oct4, SOX, PcG proteins
Is terminal differentiation irreversible or reversible?
Generally irreversible but can be in some cases reversible
What are the stages of cell type in the asymmetric stem cell division pathway?
- Stem cell divides into one identical copy plus more specialised cell
- Restricted potential stem cell, does same
- Progenitor cell
- Terminally differentiated cell
What would you see if you looked at a growing stem cell population?
Would see lots of different cell states
What are early stem cell stages and late stem cell stages associated with?
Early stages being proliferative and later being more specialised/differentiated
What was found in small quantities in most tissues?
Adult stem cells
Normally are adult stem cells proliferating?
No - they are suppressed unless needed to heal etc
How may stem cells be involved in cancer?
- Mutations occur at stem cell stage early in the pathway
- These are passed onto daughter cells as you move down pathway
- Stem cells move around the body which aligns with cancers metastasising
How are adult stem cells suppressed?
- Sit in a stem cell niche of nurse cells around the outside which suppress growth
- inhibition can be temporarily released if we need the stem cells
Correlation between proliferation and differentiation
As the pathway progresses, the proliferative capacity of stem cells drops and the degree of differentiation increases
How could we use the correlation between proliferation and differentiation to potentially treat cancers?
- if we can be sure that proliferation is inversely correlated with proliferation we could push the cancer cells into a greater degree of differentiation to supposedly stop the growth of the tumour
What are adult stem cells responsible for in the tumour?
Think responsible for producing the bulk of the tumour which is then differentiated but that the mutations occur in the stem cells
What feature of stem cells can account for the heterogenicity of tumours?
Their asymmetric divisions
How long do stem cells last?
For life
How can stem cells proliferate if they are controlled by a niche?
- They can become niche independent
- They can become controlled by another niche
Example of a cancer which commonly finds another niche where the conditions suit its growth
Breast –> Brain
4 ways a stem cell can escape the control of the niche and become cancerous
- Expansion of the normal stem cell niche
- Adapt to a different niche allowing their expansion
- Becoming niche independent
- Shift in the programmed decline in replication potential
What are the two main pathways involved in stem cell self renewal
Wnt and Hedgehog
In the Wnt pathway, what molecule most commonly plays a role in causing cancer?
- Loss of function of APC
What does loss of function of APC cause in the Wnt pathway
- Inhibitory complex cannot form and therefore active beta-catenin which drives proliferation
Overview of stages of Wnt signalling
- Normal resting state inhibitory complex made up of Axin, APC, GSK-3 and CKI is in cytoplasm. GSK-3 can phosphorylate and ubiquitinate beta-catenin which inhibits it.
- When Wnt binds to the receptor frizzled, causes dissociation of inhibitory complex meaning GSK-3 cannot phosphorylate and ubiquitinate beta-catenin
- beta-catenin not inhibited and moves to nucleus
- in nucleus drives cyclin D transcription and cell cycle
What is the inhibitor complex in the Wnt signalling pathway made up of?
Axin, APC, CKI and GSK-3
Overview of stages of Hedgehog pathway
- In absence of Hh ligand, Patched receptor inhibits smoothened
- When Hh ligand binds to Patched it releases the inhibition of smoothened
- Smoothened signals to Gli which then itself moves into the nucleus acting as a transcription factor
What organ is particularly susceptible to mutations in APC which can cause cancer?
Intestine
(Colon cancer)
What occurs in normal intestinal function?
- Stem cells at bottom of the crypt
- Villi sit on surface at top
- Stem cells proliferate and push upwards into the villi
- these cells become transit amplifying cells (more specialised)
- Continue up to top they become more differentiated until at the top of the villi you have differentiated epithelial cells,
- Die through apoptosis and are replaced by cells coming up.
How does loss of function of APC in the intestine show that tumours are derived from the stem cells?
- Found that if you mutated APC later on in the partially differentiated cells you didn’t get tumours forming
- if you restored APC function in the crypt cell, you suppressed tumour growth indicating APC might be the initiator mutation which then destabilised the DNA In the pathways allowing the cells to acquire other mutations and become cancerous
- has to happen in the stem cells
What ways can we target the Wnt pathway in cancer? (3)
- Wnt ligand receptor inhibitors
- Axin inhibitors
- B-catenin inhibitors
Example of Wnt ligand and receptor inhibitors
Porcupine - decrease Wnt ligand secretion
mAb to Wnt receptor or ligand
Example of Axin inhibitor
Tankyrase (PARP inhibitors) stablise axin
Why is it difficult to target Beta-catenin?
- Have to get these into the nucleus as that is where B-catenin goes
In a normal chromosome explain the significance of telomeres in replication
- DNA polymerases cannot copy right to the end of
the chromosomes the telomeres shorten on each cell division. - When the telomeres get too short they are eventually recognised as damaged DNA and p53 is activated to induce senescence or even apoptosis
What is a telomere?
tandem repeats found on the ends of chromosomes
and aid chromosomal replication
What is the significance of telomerases in cancer stem cells?
- Stem cells have telomerases
- They can replace chopped off bit of telomere after replication
- Tumour cells express telomerases and so are able to repair chromosomes so extending cell life
Where do the telomerases in cancer cells come from if they aren’t present in somatic cells?
- Cancer cells may have re-switched on the ability to make telomerase enzymes
- or may have never lost them as they are derived from stem cells
What is a telomerase?
- Telomerases are reverse transcriptase enzymes containing an RNA template to add TTAGGG repeats to chromosome ends
- Telomerases are found in rapidly dividing and germ line cells, most somatic cells lack telomerases
What is the benefit of somatic cells not having telomeres but rapidly dividing cancer cells having them?
Some thing to target
What do telomerase mean for prognosis
poor prognosis
How does the stem cell derivation of tumour cells make treating them difficult?
- heterogeneity in tumours
- agents may kill off 99% of the mass but not the stem cells in the middle of the mass which are making the tumours therefore they come back
How can ABC cause challenges targeting cancer stem cells?
- Most stem cells express ATP binding cassettes called ABC transporters which pump out drugs and chemicals
- Can cause resistant to these drugs
- trying to develop adjuvant inhibitors of ABC
Therapeutic challenges when targeting cancer stem cells
- Heterogeneity of tumour mass
- Potential of harming WT stem cells
- Drug resistance ATP-binding Cassette (ABC) transporters
What does loss of APC cause in Wnt?
- Loss of APC means inhibitory complex cannot form
- Thus even in absence of Wnt there is active beta-catenin which drives proliferation
What 2 pathways are commonly signalled in stem cell self renewal?
Wnt and Hedgehog
- Often active in cancer cells
What can mutations of Wnt and Hedgehog lead to?
Constitutive proliferation leading to cancer
What does loss of function of APC lead to?
(context of Wnt signalling)
- Proliferation
- inhibitory complex cannot form in Wnt signalling so beta-catenin drives proliferation
As well as APC LOF what can also cause cancer in Wnt pathway?
Overexpression of Wnt
