Cancer, Stem Cells + Cancer Stem Cells Flashcards
What is a stem cell?
= undifferentiated cells that can self-renew
= divide asymmetrically or symmetrically in response to mitogens
= involved in maintenance and repair
= terminally differentiated cells lose ability to divide
= termed post-mitotic
=often short lived
What is the stem cell hierarchy?
Totipotent cells
= e.g. zygote
= capable of giving rise to all cell types of the body ad extra-embryonic tissues
Pluripotent
= e.g. blastocyst, embryonic stem cells, induced pluripotent cells
= capable of giving rise to all cell types of the body
Multipotent Stem cells / Adult stem cells
= e.g. ectodermal, mesodermal, endodermal progenitors
= capable of giving rise to all cells of a particular tissue organ
Lineage Commited
= e.g. neuronal cell, muscle cell, lung cell
= not usually capable of giving rise to other cell types
What do transit amplifying cells do?
= carry out the bulk of proliferation
committed transit amplifying cell = progenitor cells
What is the haematopoietic system?
What happens in Leukaemia?
The hierarchical control is lost
Leukaemia = often characterised by presence of poorly-differentiated blast-like cells in blood
Defined on cell of origin
= e.g. lymphoblastic, myeloblastic, erythroblastic
Loss of differentiation often tightly linked to hyperproliferative state
Cell of origin in determining cancer / leukaemia type?
Haematopoietic system
= BCR-ABL oncogene causes
- CML if it arises in stem cell
- ALL if it arises in progenitor cell
PTC1 causes medulloblastoma whether it occurs in a neural stem cell or progenitor cell
What is the stem cell niche?
Stem cells respond to signals (mitogens) from local environment = stem cell niche
= provides a balance of growth stimulatory and inhibitory signals
= niche often located in region of tissue protected from external damage
(e.g. intestinal crypt, limbus, basal layer of skin)
What is an example of a stem cell niche?
e.g. Wnt signalling in normal and APC null colon crypts
WT
= B-catenin: Tcf/Lef ON = target genes induced by Wnts
= proliferating, undifferentiated progenitors
= B-catenin: Tcf/Lef OFF = Cell cycle arrested, differentiated cells
APC KO
= cannot switch off B-catenin: Tcf/Lef = hyperproliferation
= APC or B-catenin mutation = progenitor-like phenotype site of future polyp formation
= can result in FAP
What is Familial Adenomatous Polyposis (FAP)?
Germline mutations in APC associated with FAP
= autosomal dominant
= 100% penetrant
= relatively rare
= patients show early development of 100-100s of polyps
(EXTRA READING)
= FAP linked to defects in stem cell niche
= mutations in genes involved in stem cell regulation (e.g. APC and Wnt) = linked to development of FAP
What is the cancer stem cell hypothesis?
(Normal) Clonal evolution model
= tumours are heterogenic (mix of cell types)
Cancer stem cell model
= not all cells recapitulate tumour heterogeneity
(EXTRA READING)
=tumours are hierarchically organised, contain small population of cells with stem cell-like properties responsible for tumour initiation, growth and recurrence = CSCs
= can self-renew, differentiate into various cell type within tumour = much like normal stem cells
Cancer Stem Cells in AML?
Bonnet and Dick, presented in mid 1990s
Later presented first CSC detected in AML
= only subpopulation of human AML cells were able to proliferate in the NOD/ SCID mouse model (CD34+ / CD38-)
What is Fluorescence-Activated Cell Sorting (FACS)?
(EXTRA READING)
=can isolate and sort cells based on physical and chemical properties using fluorescent dyes and laser technology
= cells labelled with fluorescent dyes or antibodies that target specific surface / cellular molecules
= cells sorted based on fluorescent properties
= can identify CSCs = then use in xenograft assays
= show long-term self-renewal capacity
What is Cancer Cell Plasticity?
Cells are able to navigate the hierarchy , can differentiate
(EXTRA READING)
= e.g. MET and EMT (metastasis)
can also undergo dedifferentiation = loss of specialised features - return to more stem cell -like state
What are the (4) key concepts in the cancer stem cell model? (Batlle and Clevers, 2017)
- Cellular heterogeneity observed in tumours results from its hierarchal organisation
- Hierarchies driven by rare, self-renewing CSCs, whereas bulk of tumour composed of non-CSCs
- CSC identity hardwired (seen by non-CSCs seldom initiating tumours in xenograft assays)
- CSCs are resistant to standard chemotherapy and radiation treatment, preferentially target non-CSCs - a phenomenon that explains relapse after treatment
(EXTRA READING)
= also PLASTICITY = CSCs undergo genetic and phenotypic changes in response to environmental cues
= also DIFFERENTIATION = CSCs differentiate into various cell types
= also TUMOUR-INITIATING ABILITY = CSCs initiate tumour growth (linked to recurrence)
Characteristics of CSCs?
CSCs = subpopulation of tumour cells , identified through expression of surface markers
(e.g. CD24, CD44, CD133, EpCAM = cell membrane glycoproteins)
Stem cells signals like MSI can be genetically + epigenetically modified in cancer
= MSI represses expression of NUMB which normally promotes differentiation
= oncogenic activation of MSI leads to aggressive undifferentiated state
= MSI2 activation seen in blast crisis in CML
(EXTRA READING)
= self-renewal
= differentiation
= tumour-initiating ability
= resistance to therapy
= increased tumorigenicity
= heterogeneity
= plasticity
What is the significance of CSCs?
Repsonsible for majority of cancer cells in a tumour
= BUT themselves do not comprise the tumour bulk
If CSCs not eliminated by cancer treatment
= will quickly repopulate the tumour
How do CSCs resist treatment?
through “stemness”
CSCs have elevated drug efflux and DNA damage surveillance / repair
What other selective advantages do CSCs promote?
Perivascular niche
= CSC promotes angiogenesis
Hypoxic niche
= CSCs can survive in low oxygen
