Cancer stem cells Flashcards
What are the two essential properties of stem cells?
- self renewal
- differentiation into specialised cells
What do haematopoetic stem cells differentiate into?
- myeloid or lymphoid progenitors
- RBCs, platelets etc
- immune cells
What is replicative senescense?
each differentiated cell divides a certain number of times before it undergoes apoptosis
What is the ratio of cell birth to cell death?
- usually equal
- becomes unbalanced in cancer
Define
- benign
- malignant
- metastatic
- non-invasive
- locally invasive
- spread to other organs or tissues
What is clonal expansion?
- multiplication of specific cells
- rapid amplification
- clones of this cell grow and live with the normal cells
- clones acquire further mutations to form new clones with more survival advantage
- can lead to malignancy + metastasis if cells with these properties are amplified
- one cell acquires a mutation that gains a selective advantage
What are 4 factors that cause cancer?
- viruses
- muatations in specific genes
- breakdowns in immunity
- other infectious agents
- affect TSGs or cell cycle genes
What are the main problems with mammalian regeneration?
- cancer risk (this lecture)
- lost or altered genetic programme
- smaller stem cell pool
What is dedifferentiation?
- specialised somatic cells gaining stem cell properties
- some animals use this for body part regulation (newt, planaria, blastema)
- in humans, dedifferentiation leads to cancer formation
- found that tumour cells can be non-specialised cells - acquire stem-cell-like behaviour
How many cancer cells are capable of extensive proliferation ?
- a small subset
- in liquid tumours, very few isolated cells can form their own colonies
- in solid tumours, a large number of cells and cell types are required to grow tumours in xenograft models
What are the basic stages of cancer stem cell evolution?
- de novo mutations cause primary cancer and may cause primary CSCs
- additional genetic/epigenetic changes due to chemo or disease progression leads to secondary tumours and metastatic CSCs with highly variable properties
Where could cancer stem cells come from?
- transformation in normal SCs
- dedifferentiation
- either way many mutations required
- progeny of CSCs arent normal cells but are less proliferative than CSCs like normal progenitors are to normal SCs
What are the sources of heterogeneity in cancer?
- genetic/epigenetic changes and clonal evolution
- environmental effects on cancer cells
- cancer stem cell model
- in aggressive tumours -> a combination of all of these where mutated cells become CSCs - more heterogeneity
What differences in division are associated with cancer stem cells in early stage tumours?
- normally want asymmetrical division 1 stem 1 differentiated
- early cancer mutations can disrupt the ratio for example downregulation of miR-34a in breast cancer can stop its ability to inhibit proteins involved in stemness and tumorigenesis such as Nanog
How do CSCs affect the tumour - diagram?
- not mutually exlusive don’t always have these properties
What are haematopoetic stem cell cancers?
- leukaemias from stem cells
- depending on where the hit is in normal blood cell development changes the leukaemia produced
- in HSCs or progenitors lead to different leukaemias
Give two other examples of cancers that can involve stem cells?
- brain cancer
- breast cancer
What is a cell niche?
- microenvironmental cells that nurture stem cells and maintain tissue homeostasis
- sequesters cells from stimuli that cause their differentiation, apoptosis and other stimuli that would alter stem cell reserves
- in cancer the niche may adapt to provide for cancer SCs
Name 3 pathways involved in self-renewal that are degulated in cancer stem cells?
- wnt deregulated in colon cancer
- shh
- notch
- can be targeted or act as markers
How can cancer cells be de-stemmed to slow/halt progression?
- inducing differentiation (e.g. small molecule drugs or retinoic acid)
- inhibiting self renewal (e.g. inhibiting STAT3)
What kind of mutations give a cancer cell a selective advantage over neighbours?
- increased growth, division, movement
- decreased cell death
- need most/all of these to become cancer cells
How long do different cell types last?
same as regen med - intestine, blood, brain, stem cell contribution and cancer risk. somatic cells undergo a limited number of divisions before dying and are being constantly renewed
