L8 - Biology of Stem Cells, Ageing and Cancer Flashcards
What are the two different types of ageing?
Not only related to old age
Post-embryonic development – growth
What is patterning?
Patterning - small scale followed by growth
Cell patterning events, e.g. action of morphogens, function over a limited range
The final shape and size of an organism is determined by?
Growth
Growth can occur in which 3 ways?
Proliferation Cell enlargement - Cardiac hypertrophy - Skeletal muscle Accretion - Bone - ECM is laid down outside the cell
What are the 5 phases of the cell cycle?
G1 - cell enlarges S - DNA is replicated G2 - together G1, S and G2 phase = interphase M - cell divides G0 – resting phase
What is the cell cycle driven by?
Cyclins which activate CDKs
These in turn control proteins that trigger events of each phase
Cyclins fluctuate in concentration
At what stage of the cell cycle are fully differentiated cells found?
Usually in G0 and do not proliferate
How is cell division in Drosophila intrinsically controlled?
Drosophila initially develops as a syncytium – single cell with multiple nuclei
- Nuclei go through rapid synchronous cell cycles - only S and M phases
- At 14th cycle the cycle slows and G2 phase introduced
- Nuclei migrate to periphery and get surrounded by involuting cell membrane - cellularization
- Depending on its precise position, each cell will acquire its own cell division rate
- Groups of cells with similar fates will show similar division cycles - mitotic domains - Cell division in these domains is controlled by a protein – String
What is string?
Phosphatase that activates CDKs
During first 13 divisions uniformly distributed maternally-supplied string
After 13th division zygotically expressed string produced under control of patterning genes
Why is mesoderm one of the first domains to express string but 10th domain to divide?
Due to a protein call tribble - an inhibitor of string
- Tribble is induced by mesoderm inducing genes
- Functions to promote invagination by preventing cell division at inappropriate times
What are mitotic domains controlled by?
String expression
PO4-ase
Activate CDKs
What is string controlled by?
Patterning genes - Gap, Pair rule, segment polarity
What does control of growth depend on?
The organ
What is the difference between thymus intrinsic and spleen systemic?
Thymus intrinsic
- If additional thymus glands are transplanted all organs maintain their size
- Multiple amounts of tissue will be present
Spleen systemic
- If additional spleens are transplanted both spleens will only grow to half the size
- Total amount of tissue remains the same
In animals what is growth dependent on?
Absolute dimensions, not cell number is important
Ploidy affects cell size but not overall size of an animal
Dependent on morphogens, not growth factors –> steepness of morphogen gradients
What happens if limb bud is transplanted between two species of newt embryos
Intrinsic growth characteristics maintained
What are the two growth control pathways?
TOR pathway –> cell size growth
Hippo pathway –> limit organ size
What happens when the Hippo pathway is inactive?
Yki/Yap/Taz in the nucleus stimulating growth and survival of cells
Various factors lead to inactivation – mechanical stress, other signalling pathways
What happens when the Hippo pathway is active?
Yki/Yap/Taz excluded from nucleus
Various factors lead to activation - cell cell contact, cell polarization
What happens in a hippo mutant?
lLst growth restriction – Yki in nucleus
What is the size of different parts of the body controlled by?
Controlled by rate and duration of growth - declining rate then second spurt
Examples of the two stage growth in humans and pygmies
Both boys and girls grow rapidly initially, growth rate then drops until puberty sets in
In pygmies second growth phase does not occur – explains their short stature
How is the size of the Drosophila controlled?
Size of adult determined by size of larva
Insulin affects duration and rate of larval growth
- Insulin deficient flies remain smaller – smaller cells and fewer of them
Edcyson induces metamorphosis
Genome analysis in dogs have identified which pathways as main determinants of size differences between breeds?
The IGF and GH pathways
Human and dog loci linked to the IGF and GH pathways?
In human GWAS studies many more loci have been identified but most have only minor effects
The few loci identified in dogs breeds, may be the result of strong selection by humans of rare variants
In humans which hormones control growth pattern?
Insulin-like growth factors 1/2
Growth hormone
What sort of growth does growth hormone control?
Post embryonic
What is growth hormone production stimulated by?
Growth hormone releasing hormone
What is growth hormone inhibited by?
Somatostatin
Many of growth hormones effects are mediated via?
Insulin-like growth factors
How does growth hormone feed back on its own production?
Promotes somatostatin and inhibits growth hormone releasing hormone
How was it shown that the maternal environment effects fetus development in the womb?
Followed babies exposed to famine early mid and late gestation
- Early exposure
- Weight and size compensated
- Increased risk for obesity, diabetes, CHD
What is the difference between a foal of a shire and Shetland if the mother is either breed?
A Shetland - foal is smaller
A Shire - foal is larger
However both will grow to the same size
How was it shown that in humans inadequate growth in utero can lead to lifelong consequences?
Short period of severe food deprivation in the Netherlands
How do some animals not directly develop into an adult form?
Many insects develop a larval form - adult structures hidden as imaginal discs
What is the difference between the signals involved in early and post-embryonic development?
Signals involved in development
- Short range and small size
Signals involved in post embryonic development (molting and metamorphis)
- Influences from environment act on the CNS
- CNS in turn produces hormones
How do arthopods grow?
The cuticle of arthropods is rigid and does not allow growth - larvae of insects have to molt to grow
What is the molting process known as?
Ecdysis
Molting method
- Intermold stages are called instars
- Initiated by activation of stretch receptors in the cuticle
- Leads to release of protothoracicotropic hormone from corpus alatum
- Leads to release of ecdyson from the protothoracic gland
How is metamorphis controlled in tadpoles?
Change in the balance of prolactin and thyroxine causes metamorphosis
How is metamorphis controlled in insects?
- Nutrition, temperature and light
- Act via the hypothalamus affecting the levels of juvenile hormone and ecdysone
- Juvenile hormone prevents metamorphosis
- Ecdysone promotes metamorphis
- Secretion of corticotropin releasing hormone which acts on pituitary cells
- Secretion of thyroid stimulating hormone which acts on the thyroid
- Secretion of thyroxin
- Positively feeds back on itself - if certain levels reached metamorphosis becomes irreversible
- Causes growth of the limbs but degeneration of the tail
- Modulates responsiveness to other signals e.g. estrogen
In what tissues is cancer most common in?
In tissues that continue to divide throughout life
- Cell division can lead to copying errors
Where do most cancers occur?
Epithelia and blood
85% of cancers occur in epithelia
Failure in normal differentiation process that occurs during development or maintenance
Usually mutations acquired - teratoma
Teratoma cancer cell characteristics
Teratoma cancer cells can give rise to tissues from all three germ layers
In mice - murine teratoma cells transplanted to embryos and can participate normally in the formation of the animal
- Not permanently transformed
What are proto oncogenes?
After activation become oncogene –> cancer
Ras, Raf, Epidermal Growth Factor Receptor, Myc
What are tumour suppressor genes?
After inactivation –> cancer
Retinoblastoma, p53, Ptc, adenomatous polyposis coli, Von Hippel Lindau
How can developmental signals cause cancer?
Negative regulators of developmental signal transduction pathways
- Ptc regulating Hh
- APC regulating Wnt
These pathways also play a role in stem cell renewal
Examples of aberrant development signals that drive cancer
Activated Wnt - colon cancer, hepatocellular cancer
Activated Hh - basal cell carcinoma, medulloblastoma
Activated Nodal - melanoma
Activated Notch - leukemia
Activated EGF - lung cancer, breast cancer
BRCA1, BRCA2, P53
- Mutations in tumor suppressors or oncogenes that lead to genome instability
- Resulting mutations may lead to aberrant developmental signals
Which type of gene is the basis of a class of dominant hereditary diseases?
Tumour suppressor genes
Patients inherit one defective copy of the gene
Will lead to excessive cell proliferation and can ultimately result in cancer
