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
How can cancer potentially arise from differentiated cells?
Differentiated cells may reacquire the ability to self-renew
genetic reprogramming of somatic cells leading to the development of iPSCs
mutations in growth and developmental pathways (e.g. Wnt pathway, beta catenin) - may account for the reactivation of these pathways in progenitor and differentiated cells
What is the cancer stem cell hypothesis?
- Can get proliferation of the niches, so when active, they produce more progenitor cells that contribute to the growth of the mass
- If they switch to a different niche, they might be less readily suppressed in their growth
- Ties into the metastatic aspect of the cells
- Stem cells are very mobile during embryogenesis
- New niche is not suppressing the cells properly, so they become metastatic
- Could become niche-independent, or could act normally but they forget to switch off their self-renewal pathways
Describe the Wnt signalling pathway
- In the absence of Wnt, got ubiquitination of beta-catenin and it cannot translocate to the nucleus
- Get no self-renewal genes
- In the presence of wnt, dissociation of the inhibitory complex occurs, and beta catenin is able to translocate to the nucleus
- Tcf component of the complex is one of the main targets
- In cancer cells, get loss of expression of the APC component – means the inhibitory complex cannot form – even in the absence of Wnt, there is nothing to phosphorylate and sequester beta catenin
Describe the Hh pathway
- Beta catenin binds to cyclin D, which drives the cell cycle
- Can get over-expression of wnt, which would have the same function
- Patched/smoothened pathway – In resting cells, patched inhibits smoothened
- Hh can bind to patched, which releases smoothened
- Could see overactivation of the gli TF
Describe differentiation of intestinal villi cells
- Showed that mutating APC in crypt cells caused tumours but not in prog or differentiated cells
- All the daughter cells produced from it would have the mutation
- This showed it is the initiating mutation that is required for the formation of colon cancer
- Restoring APC function, restores crypt cell function even in presence of other mutations
What are polycomb proteins?
Polycomb proteins are the ‘guardians of stemness’ - they drive self-replication and repress differentiation
they repress tumour suppressor genes (e.g., CDKI, INK4)
PRC1 is a PcG complex (e.g. bmi) - it ubiquitinates H2a, suppresses transcription, compacts chromatin so there is no accessibility for TFs
PRC2 (e.g. EZH1, SUZ12) histone methyltransferase activity, targets histone 3 - represses the expression of differentiation genes
What is some evidence for PcG proteins in cancer?
Bmi over expression and amplification is seen in many cancers, such as laeukaemias and lymphomas
PcG protein repressor of Bmi is shown to be essential for control of self-renewal in HSCs
It is very challenging to target
How is acute promyelocytic leukaemia (APL) caused?
In the absence of retinoid acid, get recruitment of HDAC and gene repression
In the presence of retinoic acid, get recruitment of coactivator and expression of genes for differentiation
APL is caused by fusion of PML to RAR
PML-RAR recruits HDAC and represses even in the presence of RA - repression of differentiation
p53 function of PML is also lost, so there is no cell cycle arrest and no apoptosis
What is the experimental evidence for cancer stem cells?
Despite being clonal, CSCs can give rise to a range of cells in various stages of differentiation, such as teratocarcinomas
express both normal stem cell markers HSC/CSC (CD34+, CD38) - tricky to isolate stem cells
Developmental plasticity - EMT transitions
