Wk 9: Hallmarks of cancer Flashcards
Outline the properties of carcinoma in situ
- Loss of stratification
- Immature cells
- Basement membrane intact
- Cellular dysregulation
- No longer perform specialist function
What were the original hallmarks of cancer?
- Sustaining proliferative signaling
- Evading growth suppressors
- Activating invasion + metastasis
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting cell death
What are the emerging hallmarks of cancer?
- Avoiding immune destruction
- Tumour promoting inflammation
- Genome instability + mutation
- Deregulating cellular energetics
What is cellular growth controlled by?
- Mitogens - stim cell division
- Growth factors - stim cell growth
- Survival factors - suppress apoptosis
What are the major components of the cell cycle?
- M phase (mitosis) - cell division
- Interphase - cell growth + DNA replication
- Check points
What is the cell cycle?
- Duplicate DNA/C’some
- Prod 2 identical daughter cells
- Synthesis: 10-12 hr
- Mitosis: <1h
Outline the cell cycle
- G1 (interphase)
- S (interphase)
- G2 (interphase)
- M
What is the G1 phase?
- Longest
- After M phase, cells = half size
- Cells adapt + grow to normal size
- Cells repressed + can’t undergo further division
- Poor nutrition/anti-proliferative signal = enter G1
What is the G0 phase?
- Cell cycle arrest
- Become specialised
- Cells active (prod protein, enzyme)
- Can reenter cell cycle if gene activated
Which cells can’t leave G0 phase?
Skeletal + neuronal cells
Which cells are always in G0?
Liver cells
- Tissue don’t express genes encoding CDK + cyclins
- If damaged, mitogens released, enter G1 + release CDK
What is the S phase?
DNA replication
What is the G2 phase?
- Checkpoint (DNA integrity)
- Enzymes activated
- Trigger mitosis
- If faulty, prevent from entering M phase
What occurs in the M phase?
- Prophase
- Prometaphase
- Metaphase
- Anaphase
- Telophase
Prophase
DNA disentangle + condense (sister chromatids)
Prometaphase
C’some migrate to equatorial plane in midline
Metaphase
C’some align along metaphase plate of spindle
Anaphase
Centromere divide + sister chromatids pulled apart
Telophase
- Nuclear membrane reforms
- C’some uncoil + diffuse
- Spindle fibre disappears
What happens when DNA is damaged?
- Cell cycle arrest + activate DNA damage response
- Apoptosis
What is the cell division cycle 2 (cdc2) protein essential for?
Cell cycle progression during:
- G1 -> S
- G2 -> M
What coordinates the progression of the cell cycle?
Cyclins + cyclin dependant kinase (CDK)
Outline the classes of cyclins + what they do
- G1/S - activate CDK in late G1
- S - Activate CDK in S + elevated until mitosis
- M - activate CDK in G2 -> M
What are the 4 major cyclins?
D, E, A + B
What do cyclins + CDK do?
- Form complex
- Phosphorylates targets
- Targets change during cell cyle
What are the cell cycle checkpoints?
- G1/S
- G2/M
- M/G1
G1/S checkpoint
Pass:
- Sufficient organelles
- Growth factor activation
Fail:
- TGFβ proliferation inhibitor
- ATP deficiency
G2/M checkpoint
Pass:
- Completely replicated genome
- Large cell vol
Fail
- DNA damage
M/G1 checkpoint
Pass:
- Equal distribution of c’some btw daughter cells
Fail:
Chromatid not assembled on spindle
Give examples of what causes DNA damage
- Lack of growth factors
- Excessive mitogenic signalling
- Chromosomal dysregulation
- Unreplicated DNA
- Microtubule spindle defects
What are CKIs?
- Bind to cyclin + CDK + distort active site of CDK
- Insert into ATP binding site + inhibit CDK enzymatic activity
Which CKIs inhibit CDK1 + 2 complexes
- p21 (prostate + colon)
- p27
- p57 (kidney + skeletal tissue)
Give examples of INK4 proteins
- p16: CDK6
- p15: CDK4
- p18: CDK 4/6
- p19: CDK 4/6
How does p53 regulate the cell cycle?
- Cell cycle arrest
- DNA repair
- Senescence
- Apoptosis
