basic developmental strategies

• external signals trigger expression of classes of genes - new proteins are synthesised which induce the cell to alter their phenotype

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

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

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

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

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

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

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