basic developmental strategies

Question 1

linear differentiation

Answer 1

• external signals trigger expression of classes of genes

- new proteins are synthesised which induce the cell to alter their phenotype

Question 2

colony formation and cell type specialisation

Answer 2

cells aggregate to form colonies and exchange signals that induce differentiation into different specialised cell types that allow division of labour

wingless and hedgehog signalling define compartment boundary

• they feedback on eachother
• wingless also promotes expression og engrailed
• in absence of wingless activity, hedgehog and engrailed are lost = loss of segment, polarity and pattern

Question 3

stem cells and cancer

Answer 3

cancer is caused by mutations
somatic cells are short lived and often post mitotic
mutations may accumulate in long lived proliferating cells
cancer causing mutations can occur in stem cells or progenitor cells

single cells are the origins of many tumours - this is consistent with somatic mutation theory

Question 4

cancer stem cell beginings

Answer 4

some tumours of reproductive organs contain a hug variety of different cell types
teratomas/ carcinomas
strains of mice spontaneously get them at high frequencies
embryonal carcinoma cells
can be transplanted to give fresh teracarcinomas
single cells

same principles that operate in normal tissue cell maintenance can also operate in tumours
can divide symmetrically or asymmetrically
cancer cells can either arise from a mutation in a stem cell or a progenitor cell with mutations which can divide to produce many more cells

Question 5

what are the 2 models that explain clonality and heterogeneity

Answer 5

stochastic model:

• malignant transformation
• progeny retain phenotype
• heterogeneity due to micro environment and mutations
• effective treatment must eradicate all cells

cancer stem cell model:

• only some tumour cells are tumourogenic
• csc self-renew and differentiate
• csc drive growth and initiate developmental programme
• treatment needs to only eradicate csc

Question 6

cancer stem cell model

Answer 6

a subset of cells able to elaborate tumour heterogeneity
number can vary
not mutually exclusive to stochastic model
- due to genomic instability
- csc subclones with different characteristics
- plasticity

evidence:
not all tumour cells are tumourogenic - autotranslplanted tumour cells in patients
cancers can differentiate - teratocarcinoma cells form chimeras
do not prove the model - prospective purification of csc is required

Question 7

CSC in solid tumours

Answer 7

breast cancers
CD44+ CD24- / low lineage - cells are tumourogenic in SUD mice
100 cells is enough
mouse cells are the same heterogeneity as originals

CD44 high/ CD24 low can be generated from CD44 low / CD24 high progenitor type cells by introducing a single transcription factor Snail or Twist

in breast cancer, Snail transcription factor expression correlates with poorer clinical outcome - more relapses seen

circulating tumour cells have epithelial and mesenchymal markers suggesting partial EMT

Question 8

clinical implications

Answer 8

resistance to treatment may be due to CSC surviving
chemo can increase CSC compartment
identification of CSC allows its study
this is a potential for targeted treatment