Lecture 4 - Stem cells, cancer, and cancer stem cells Flashcards
What do stem cells have a lot of?
Number of potential open fates - different ‘flavours’ of potency
What are stem cells?
- Undifferentiated cells that can self-renew
- Divide asymmetrically or symmetrically in response to mitogens
- Organ maintenance and repair
- Terminally differentiated cells lose the ability to divide and are termed ‘post mitotic’. They are often short-lived
Stem cell hierarchy
Highest potency: Totipotent cells - Capable of giving rise to all cell types of the body and extra-embryonic tissues
e.g. zygote
Pluripotent: Capable of giving rise to all cell types of the body
e.g. Blastocysts
Blastocyst -> Embryonic stem cells or induced pluripotent cells
Multipotent stem cells - Capable of giving rise to all cells of a particular tissue or organ
- e.g. Ectodermal, mesodermal, or endodermal progenitors
Lineages committed - Not usually capable of giving rise to other cell types:
Ectodermal progenitors -> Neuronal or pigment cell
Mesodermal progenitors -> Muscle or blood cell
Endodermal progenitors -> Lung or pancreatic cll
The hematopoietic system
Multipotent hemopoietic stem cell -> Multipotent hemopoietic progenitor
Why is hierarchical control lost in leukaemia
- Characterised by large presence of poorly differentiated blast-like cells in the blood
- Leukaemia are defined based on the cell of origin e.g. lymphoblastic, myeloblastic, or erythroblastic
e.g. chronic myeloid leukaemia
Chronic phase -> accelerated phase -> blast crisis
Hyperproliferative state
Hematopoietic stem cell -> common myeloid progenitor or mutation
Common myeloid pregenitor -> typical development -> monocyte, neutrophil, basophil or eosinophil
Mutation -> additional mutation -> blocked differentiation that causes leukaemia
Cell of origin can be important in determining cancer type
- Mutation in haematopoietic stem cell
BCR-ABL -> Stem cell -> CML
Stem cell -> (BCR-ABL->) progenitor cell -> B-ALL
a. In the haematopoietic system, the BCR-ABL oncogene causes chronic myeloid leukaemia if it arises in a stem cell but B cell acute lymphocytic leukaemia if it arises in a progenitor cell
Mutation in neural stem cell
PTC1 -> Stem cell and PTC1-> progenitor cell causes medulloblastoma
In contrast, loss of PTC1 causes medulloblastoma whether it occurs in a neural stem cell or progenitor cell.
The stem cell niche
Refers to a microenvironment, within the specific anatomic location where stem cells are found, which interacts with stem cells to regulate cell fate.
The niche provides a balance of growth stimulatory and inhibitory signals
The niche is often located in a region of tissue that is protected from external damage (e.g. intestinal crypt, limbus, basal layer of skin)
APC, tumour suppressor mutated in CRC
APC - Adenomatous Polyposis Coli
Tumour suppressor gene
Antagonist of the Wnt signalling pathway
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 the same histological type exhibit different molecular profiles (reflects germline and somatic mutation profile – environmental effects etc)
Interpatient - different primary tumours in different patients
Intermetastatic - Different metastatic tumours in different locations
Intratumour heterogeneity
Cancer cells within a single tumour exhibit molecular heterogeneity. Due to genetic, transcriptomic/proteomic, epigenetic and/or phenotypic differences
The cancer stem cell hypothesis
Stochastic model:
Tumour -> Cell type separation
Cell type separation -> Outgrowth by unlimited cell division and differentiation
All isolated tumour cells have the capacity to differentiate indefinitely and form new tumours
Cancer stem cell model:
Cancer stem cell - > Self-renewing cancer stem cell -> unlimited division -> tumour forms
cancer cells that don’t self-renew don’t form tumours due to limited cell division and differentiation
