Cancer Stem Cells Flashcards
What are the origins of a cancer cell?
When there are aberrations in proliferation, differentiation and apoptosis, altering the balance and resulting in accumulation of non-functional cells.
What are the problems with the somatic cell hypothesis?
States:
Cancer is a disease of proliferating cells, but most mature cells do not proliferate.
Tumours are often heterogeneous in terms of cellular differentiation but cancers are clonal.
Cancer is caused by accumulation of mutations in single cell, but most cells have finite lifetime and do not live long enough to acquire 3+ mutations.
Only a small number of tumour cells can recolonise, but there is no way for them to get appropraite growth signals at the secondary site.
What are stem cells?
Pluripotent cells which differentiate into many different cell types.
They are unspecialised cells which can produce themselves and generate more specialised cells and intermediate cells which results in specialised cells which often cannot divide.
The terminal differniation is generally irreversible and change in cell state is transcriptionally regulated.
What are adult stem cells?
Blood, intestine, skin, muscle, liver and more.
In bone marrow the haemopoietic stem cells are required for normal cell turnover.
In liver and muscle, stem cells are involved in healing.
They are present in small numbers are proliferation is normally suppressed.
They are difficult to identify and isolate.
Why could stem cells be involved in cancer?
Undifferentiated or partially differentiated stem cells are implanted into tissues and they can form tumours.
For a differentiated cell to form a tumour it must dedifferentiate and reacquire ability to proliferate.
Mutations may occur in adult tissue stem cells.
They proliferate rapidly and undergo some degree of differentiation and metastasise more easily.
How are stem cells regulated?
Stem cell proliferation is regulated by niche cells which secrete factors which suppress or stimulate stem cells to proliferate.
Cancer stem cells can become niche-independent or under control of different niche.
Stem cells can also self renew or differentiate.
Pathways are controlled by transcription factors which upregulate or suppress self-renewal or differentiation genes.
What is the Wnt pathway?
Wnt is a proto-oncogene which is mutated in 90% of colon cancers causing loss of function and increased beta catenin activity.
It binds to rec Frizzled sequesters GSK-3 releasing beta catenin to act as a transcription factor to drive c-myc and cyclinD expression and proliferation.
What is hedgehog pathway?
Sonic, desert and indian bind to patched and release the inhibition of smoothed. The signaling pathway release Gli transcription factor to drive proliferation.
Over expression of hedgehog or Gli, or a loss of function of patched causes cancer.
What happens when wnt or Hh is added to signaling pathways?
When wnt is added to the pathway it phosphorylates the receptor leading to breakdown of inhibitory complex and the complex then falls apart. Beta catenin is free and no longer phosphorylated so can go to the cell cycle and activate cyclin D.
Hh binds to patched and smoothed is then free which enables it to activate Gli which goes to the nucleus.
How is wnt targeted in cancer?
Ligand and receptor inhibitors:
Axin inhibitors
B-catenin inhibitors
What are telomerases?
Telomerases are reverse transcriptase enzymes which contain RNA template to add TTAGGG repeats to chromosme ends.
They are tandem repeats found at the end of chromosomes which aid chromosomal replication.
They shorten on each cell division.
When they are too short they are recognised as damaged DNA and p53 is activated to induce senescence or apoptosis.
They are found in rapidly dividing and germ line cells.
What is the link between telomerases and cancer?
Tumour cells express telomerases so can repair chromosomes extending cell life.
Can be treated using telomerase antisense and G-quadruplex stabilising ligands.
