Lecture 4 Flashcards
What do stem cells come in different ‘flavours’ of?
Potency - number of open fates
Adult stem cells can’t become any type of cell unlike embryonic stem cells
What is a stem cell and their function
Undifferentiated cells that can cell-renew
Divide symmetrically or asymmetrically in response to mitogens
Organ maintenance and repair
Terminally differentiated cells lose abilities to divide and termed post-mitotic - short lived
Stem cell hierarchy
Totipotent cells - Capable of giving rise to all cell types of the body and extra-embryonic tissues
Pluripotent - Capable of giving rise to all cell types of the body
Multipotent - Capable of giving rise to all cells of a particular organ or tissue
Lineage committed cells - Not usually capable of giving rise to other cell types
Examples of cells in stem cell hierarchy
Zygotes (totipotent) -> Blastocysts (plutipotent)
Blastocysts develop into embryonic stem cells or induced pluripotent cells
These cells then develop into ectodermal, mesodermal, or endodermal progenitors (committed transit amplifying cells) to give rise to adult stem cells (multipotent)
Adult stem cells differentiate into specialised cells e.g. neuron or pigment cells (ectodermal), muscle or blood cells (mesodermal), lung or pancreatic (Endodermal) which are lineage committed
Stem cells in the haemopoietic system
Multipotent haemopoietic progenitors develop into common lymphoid or myeloid progenitors
Lymphoid progenitors further divide and differentiate to form NK cells, B cells, dendritic cells, or T cells (thymus)
Myeloid progenitors further divide and differentiate to form erythrocytes/megakaryocyte, mast cells/basophils, eosinophils, neutrophils/ dendritic cells/ monocytes (which develop into macrophages/osteoclasts).
In leukaemia, how is hierarchical control is lost?
- Characterized by large amounts of poorly-differentiated blast-like cells (immature progenitors) in blood
- Classified on cell of origin e.g. lymphoblastic, myeloblastic, erythroblastic.
Development of leukaemia
Haemopoietic stem cell -> common myeloid progenitor or mutation
CMP -> typical division and differentiation to form monocytes, neutrophils, eosinophils, basophils/mast cells
Mutation -> Excessive division (hyperproliferation) and blocked differentiation, forming tumours
Cell of origin in determining cancer types
BCR-ABL oncogenes:
Mutation in haemopoietic stem cell -> chronic myeloid leukaemia
Mutation in progenitor cell -> B-ALL
PTC1 tumour suppressor genes:
Stem cell and progenitor cell lead to medulloblastoma
Stem cell niche
Microenvironment within specific anatomical location where stem cells are found, which interact with stem cells to regulate cell fate
Niche provides balance of growth stimulatory and inhibitory signals
Located often in region of tissue protected from external damage e.g. intestinal crypts
Loss of APC (Adenomatous polyposis coli), tumour suppressor mediated in Colorectal cancer
Wnt, phosphorylated LRP, Frizzled, Dishevelled and axin bind to form a complex
Inactive GSK-3beta (as phosphorylated axin isn’t bound), APC, B-catenin, and Wtx all then form a complex, preventing degradation of B-catenin.
B-catenin passes nuclear membrane and binds Tcf/Lef transcription factor on DNA, allowing for transcription of proliferation genes as Groucho is not bound instead.
Familial Adenomatous Polyposis
Germline mutations in APC associated with Familial Adenomatous Polyposis (autosomal dominant). 100% penetrance – i.e. all develop cancer
FAP is relatively rare (<1% of colon cancers)
Intertumour heterogeneity
Different tumours of same histological type exhibit different molecular profiles (reflects germline/somatic profiles - environmental effects)
Intratumour heterogeneity
Cancer cells within single tumour exhibit molecular heterogeneity
Due to genetic, transcriptomic/proteomic, epigenetic and/or phenotypic differences
Stochastic model in cancer stem cell hypothesis
Tumour -> Cell type separation -> Outgrowth via unlimited cell division and differentiation
All isolated tumour cells have capacity to differentiate indefinitely to form new tumours
Cancer stem cell model in
Cancer stem cell -> cell type separation (where one set self-renews) -> Self-renewing
cancer cells lead to unlimited cell division and differentiation, and all others lead to no tumour formation
CSC in acute myeloid leukaemia
Bonnet and Dick (1997)
First bona fide CSC identified in AML
Used xenotransplantation model
Only subpopulation of human AML cells could proliferate in NOD/SCID mouse model: CD34+ /CD38-
Characteristics of cancer stem cells
Subpopulation of tumour cells that can be defined using CD24, CD44, CD133 etc
Only normal stem cells:
- Proliferation potential
- Differentiation potential
- Functional DNA repair
Only cancer stem cells:
- Abnormal proliferation
- Differentiation failure
- Unreliable DNA repair
Both cancer and stem cells:
- Self-renewal
- Cell surface markers
- Affected by Niche
What are CSC responsible for?
Majority of cancer cells in tumours but do not themselves comprise the tumour bulk
If CSCs are not eliminated by cancer treatment, they can quickly repopulate tumours.
What impact do CSCs have on treatment
Enable treatment resistance
Elevated drug efflux and DNA damage surveillance/repair using DNA repair machinery
In normal cells:
Chemotherapy is taken in by ABC transporter, leading to cell death
CD133- is exposed to radiation and killed
In cancer cells:
Chemotherapy is not taken in by ABC transporter, leading to cell survival
DNA repair machinery provides CD133- immune from death
Explain selective advantages of stem cell properties in CSCs
Perivascular niche:
Endothelial cell signalling supports CSC expansion.
CSC signalling promotes angiogenesis.
Key concepts in standard cancer stem cell models
- Cellular heterogeneity observed in tumours can result from hierarchical organization
- Hierarchies driven by rare, self-renewing CSCs, whilst tumour bulk formed from non-CSCs
- CSC identity is hardwired, as illustrated by the fact that non-CSCs seldom initiate tumours in xenograft assays
Cancer cell plasticity
The CSC plasticity model assumes that tumor hierarchy is very dynamic.
Plastic cancer cells can constantly shift between non-CSC and CSC states depending on various intrinsic and extrinsic stimuli, giving rise to a heterogeneous tumor population.
