Cancer stem cell hypothesis Flashcards
Outline the problems with the hypothesis that cancer originates from our mature differentiated cells in the body
- Cancer is a disease of proliferating cells - the rate at which mature cells proliferate is not enough to account for mutations. This is because in order for the mutation to be passed on it must be dividing.
- Tumours are a heterogeneous mass in terms of cellular differentiation (but cancers are clonal)
- cancers is caused by the accumulation of mutations in a single cell - but most cells have a finite lifetime and so don’t live long enough to acquire 3-7 mutations
- Only a small number of tumor cells can actually recolonise
What is the main problem with tumors being a heterogeneous mass of cells?
The cells may respond differently to drugs - this could lead to a few cells being left behind and cancer returning.
What is meant by asymmetric cell division?
They way in which stem cells divide.
Divides to produce one daughter cell that is exactly the same (pluripotent) and one daughter cell that is slightly more specialized. The result is a fairly heterogenous population of cells with different levels of specialisation.
Why has it been hard to identify adult stem cells in the body?
Up until recently, we had poor markers for stem cells - therefore difficult to detect and isolate. In addition there is a very small number of them as proliferation is normally suppressed until needed.
What is the stem cell niche? How are stem cells maintained in this niche so that they are not proliferating?
Stem cells reside in this niche when they are not needed. The dependence of stem cells on the niche limits their expansion - in the niche they are surrounded by nurse cells which suppress growth normally. Nurse cells release antigrowth suppressor cytokines and factors.
What happens in the stem cell niche when a tissue requires new cells?
The suppression from the nurse cells stops, allowing the stem cell to proliferate and over time there is an increase in the degree of differentiation.
Give a brief overview as to why it is thought that stem cells are responsible for cancer
Stem cells are long-lived and self-renew giving more opportunity for mutations to accumulate. The asymmetric division of stem cells may account for the heterogeneity of the tumour mass.
Adult stem cells are present at very numbers in tissues but have been shown to have the ability to recolonize.
Many of the signaling pathways involved in self-renewal have been shown to be mutated in cancer cells.
Outline the different hypothesis (4) whereby stem cell growth becomes unregulated by the niche
Expansion of the normal stem cell niche permits the expansion of cancer stem cells.
Cancer stem cells that arose from normal stem cells adopt to a different niche allowing their expansion.
Cancer stem cells that arose from normal stem cells become niche-independent and self-renewal is cell autonomous.
Shift in the programmed declined in replication potential.
Outline the Wnt signalling pathway
Wnt proteins are secreted intercellular signaling molecules that act as a ligand to trigger a specific signal transduction pathway.
In the absence of Wnt ligand, a degradation complex forms in the cytoplasm (consists of axin, GSK3B, APC and CKI). An important transcription co-activator called B-catenin is phosphorylated by the GSKB and CKI of htis complex.
B-catenin is further modified by ubiquitination via newly recruited ubiquitin ligase. This acts as a molecular flag that targets B-catenin for degradation by proteosomes. Target genes under regulation of the B-catenein TF are suppressed.
Upon binding of Wnt ligand to its receptor frizzole and co-receptor LRP, the cytoplasmic tail of LRP is phosphorylated and axin is recruited to the tail. This disrupts the assembly of the complex.
This allows B-catenin to move into the nucleus where it can act as a co-activator.
What is the relationship of Wnt signalling and colon cancer?
wnt is a proto-oncogene pathway that is mutated in 90% of colon cancers. Loss of function of APC occurs and so the degradation complex cannot form.
Normally Wnt signalling is required to maintain the stem cells of the crypt.
Colon cancer seems to follow a sequence of progression from benign polyps to carcinoma in situ and finally invasive carcinoma. This sequence is paralleled by the accumulation of mutations
The location of the initial mutation that induces constitutively active Wnt signaling has been shown to be the stem cell of the small intestine (the deletion of APC in progenitor or differentiated cells does not lead to tumour formation)
What are the three Hh proteins?
Sonic, desert and indian
What happens when Hh binds to patched? (Hedgehog pathway)
Inhibition of smoothened in relieved - the signal is then transduced into the cell and causes a large protein complex to dissociate and release the zinc finger transcription factor of ‘Gli’ so it can translocate to the nuclues and regulate the expression of its target genes.
Hh target genes include cyclin Ds, BCL12, VEGF and Snail (important for metastasis)
What is Gorlins syndrome?
Patients with gorlins syndrome carry a germ line mutation in one copy of patched (TSG) and therefore have a predisposition to develop skin, cerebellar and muscle tumours.
What are telomeres?
Telomeres are tandem repeats (non-coding) found on the ends of chromosome and aid chromosomal replication. Because DNA polymerases cannot copy right to the end of the chromosomes the telomeres shortern on each cel division.
What happens when telomers get too short?
When the telomeres get too short they are eventionally recognised as damaged DNA and p53 is activated.
