Cancer stem cells Flashcards
Stem cells
Undifferentiated cells able to divide asymmetrically in response to mitogens
Slow cycling
Long lived
Progenitor cells
Transit amplifying cells carry out the bulk of proliferation to terminally differeniated cells
Leukaemia
Hierarchical control of haematopoiesis is lost
Large amounts of poorly differentiated blast-like cells
Defined based on cell of origin (lymphoblastic, myeloid, erythroblastic)
Myc and loss of differentiation
Myc drives expression of Id TFs which are antagonists of bHLH TFs which control differentiation
Id2 sequesters MyoD (muscle specific bHLH) preventing muscle differentiation
Id downregulation required for differentiation
Cell of origin and cancer type
BCR-ABL oncogene causes CML if arises in a stem cell but B cell acute lymphocytic leukaemia if arises in a progenitor cell
PTC1 TSG loss causes medulloblastoma whether it occur in neural stem or progenitor cell
Stem cell niche
Provides balance of growth stimulatory and inhibitory signals
Often located in region protected from external damage (intestinal crypt)
Wnt
Produced by stromal cells at the bottom of the intestinal crypt
Concentration gradient of wnt through crypt determines whether cells will divide or differentiate
Absence of Wnt
APC forms a complex with Axin, GSK3 and beta-catenin
GSK3 phosphorylates beta-catenin leading to its degradation
Tcf/Lef interacts with Groucho (TF) to suppress proliferation and drive differentiation
Wnt signalling pathway
Wnt binds frizzled which recruits dishevelled.
Dishevelled sequesters axin and prevents complex formation.
Beta-catenin binds Tcf/Lef and drives proliferation
APC mutations
Somatic mutations in 2/3 of colon cancers
No longer suppresses wnt signalling pathway. Becomes active in absence of wnt
Germline mutations associated with familial adenomatous polyposis (100% penetrant)
Cancer stem cells
Small subpopulation of cancer cells are able to proliferate
Human AML (myeloid leukaemia) added to immunosuppressed mice
CD34- cells unable to produce cancer but CD34+ can
CD34+CD38+ required many cells to engraft cancer
CD38- cells caused cancer with a low number of cells
Cancer stem cells in solid tumours
High CD44, low CD24 breast cancer cells vastly more tumorigenic in NOD/SCID model
Cancer stem cell characteristics
Expression of membrane glycoproteins that are often expressed in normal stem cells
Responsible for populating tumours
Symmetric division drives aggressive growth
Stem cell treatment resistance
ABC transporter upregulation enables increased drug efflux.
Upregulated DNA repair pathways
Therapy selects for stem cells. Second treatment likely to be less effective
