lecture 6 - cancer stem cells Flashcards
How did the cancer stem cell hypothesis arise?
Cancer is a disease of proliferating cells, but most mature cells do not proliferate
Tumours are often heterogenous in terms of cellular differentiation, but cancers are clonal
Cancer is caused by the accumulation of mutations in a single cell, but most cells do not live long enough to acquire 3+ mutations
What is the definition of self-renewal?
Unspecialised cells that can reproduce themselves and/or generate more specialised cells indefinitely
Balance between proliferation and differentiation states are what drives cancer
What are some characteristics of adult stem cells and why are they difficult to detect?
They are required for normal cell turnover - need to make lots of new blood cells
Only present in very small numbers - hard to detect, proliferation is normally suppressed
Difficult to identify and isolate - restricted number of specific proteins on the surface that label them as stem cells
Residual stem cells have a high proliferative capacity
How can stem cells become cancer?
If undifferentiated/partially differentiated stem cells are implanted into tissues they can, in some cases, form tumours
Alternatively, mutations may occur in the tissue stem cells - these proliferate rapidly and metastasise more easily
The adult stem cells are normally kept in niches - they are surrounded by cells that secrete factors
What type of pathways can be targeted for therapeutics?
Self-renewal pathways are used - normally switched off when the cell differentiates
These pathways are not normally used by our cells, so they are a target for therapeutics - would spare our normal, healthy cells
How are stem cells normally regulated?
Stem cell proliferation is normally regulated (suppressed) by niche cells
These secrete factors which suppress or stimulate stem cells to proliferate
Cancer stem cells can become ‘niche-independent’ or under control of a different niche
What are the four ways in which cancer stem cells are hypothesised to arise?
1) Expansion of the normal stem cell niche permits the expansion of cancer stem cells that arose from the normal stem cells
2) Cancer stem cells that arose from normal stem cells adapt to a different niche, allowing their expansion
3) Cancer stem cells that arose from normal stem cells become niche-independent, and self-renewal is cell-autonomous
4) Shift in the programmed declined in replication potential - cancer stem cells arising from a progenitor cell
How is the Wnt pathway involved in cancer?
In the Wnt pathway, there is an inhibitory complex present in the cytoplasm (APC, GSK3, CKI and Axin). GSK3 can phosphorylate and inhibit beta catenin, which results in the ubiquitination of beta catenin and its degradation
In the presence of Wnt, the inhibitory complex dissociates so GSK3 can no longer phosphorylate beta catenin - it is now free to move into the nucleus and drive transcription
Wnt binding to frizzled receptor sequesters GSK3, releasing beta catenin to act as a TF to drive c-myc and cyclin D expression, and hence proliferation
How is the Hh pathway involved in cancer?
In the absence of the ligand (Shh, Ihh, Dhh), patched receptor will inhibit smoothened
When Hh binds to patched, this removes inhibition of smoothened, leading to release of Gli, a transcriptional regulator
How does differentiation of intestinal villi cells occur and how can they lead to cancer?
At the bottom of the crypt there are stem cells - they become more specialised as they move out, until they reach the top of the villi and can absorb nutrients
Over time, they become apoptotic and are replaced by other cells moving up the crypt
If mutated later on when partially differentiated, tumours did not form - only when mutated early on
This indicates that APC might be the initiator mutation that destabilises the DNA in the pathways, allowing cells to acquire other mutations
How can Wnt be targeted in cancer?
Porcupine inhibitors decrease Wnt ligand secretion
Axin inhibitors - stabilise axin
B-catenin inhibitors - disrupt b-catenin TF function to drive self-renewal - difficult to target as they are not enzymes so do not have active sites; need to be translocated to the nucleus
what are telomeres and telomerases?
Telomeres are short tandem repeats found on the ends of chromosomes, they aid in chromosomal replication
Because the DNA polymerases cannot copy right to the end of the chromosome, they shorten on each cell division
When too short, they are eventually recognised as damaged DNA and p53 is activated to induce senescence or apoptosis
telomerases are RT enzymes containing an RNA template to add TTAGGG repeats to chromosome ends
Cancers with high N-myc levels - cancer will be proliferating at a higher rate (potential for anti-cancer therapy)
What are therapeutic challenges that come with cancer stem cells?
Heterogeneity of tumour mass - they may kill off most of the mass, but not the stem cells - may relapse
3D/hypoxic nature of tumour mass - no blood flow so cannot deliver drugs
Potential of harming WT cells
Drug resistance ATP-binding cassette transporters - pump out exogenous drugs and chemicals, so are resistant to chemo
