Cancer - Basics
Based on undergrad Australian lecture
- Created by: nCaitlyn
- Created on: 04-11-15 10:29
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- Cancer
- Origin
- Stem Cell Model
- Cell of Origin = first cancer cell
- new differentiated cells can onl self-renew and produce more cells of its type
- CoO is stem cell that self renews and differentiates
- oncogenes and k/o TSG allow cancer cells to gain self-renewal ability through FoxO, telomerase, BRCA2/RAD50, and loss of Sox2, cMYC, DMNT3a/b
- Plasticity Model
- like stem cell model, but differentiated cells can revert to original stem cell
- melanomas present with 29% tumourigenic cells, therefore no hierarchy, therefore PLASTICITY MODEL
- Clonal Evolution Model
- all cells can self-renew and differentiate to create new cells, because genetic mutations to random cells, rather than to stem cells
- no hierarchy of heterogeneity within tumour
- cells can also revert to original form
- Experimental Tests
- dissociate tumour cells into different populations, and plant each into different mice to see which one will grow
- if only one population grows = STEM CELL MODEL
- Stem Cell Model
- Cell of Origin = first cancer cell
- new differentiated cells can onl self-renew and produce more cells of its type
- CoO is stem cell that self renews and differentiates
- oncogenes and k/o TSG allow cancer cells to gain self-renewal ability through FoxO, telomerase, BRCA2/RAD50, and loss of Sox2, cMYC, DMNT3a/b
- Stem Cell Model
- melanomas present with 29% tumourigenic cells, therefore no hierarchy, therefore PLASTICITY MODEL
- if only one population grows = STEM CELL MODEL
- dissociate tumour cells into different populations, and plant each into different mice to see which one will grow
- Stem Cell Model
- Cause
- Origin
- Plasticity Model
- like stem cell model, but differentiated cells can revert to original stem cell
- Clonal Evolution Model
- all cells can self-renew and differentiate to create new cells, because genetic mutations to random cells, rather than to stem cells
- no hierarchy of heterogeneity within tumour
- cells can also revert to original form
- Experimental Tests
- dissociate tumour cells into different populations, and plant each into different mice to see which one will grow
- if only one population grows = STEM CELL MODEL
- if only one population grows = STEM CELL MODEL
- dissociate tumour cells into different populations, and plant each into different mice to see which one will grow
- Plasticity Model
- Oncogenes
- Drive growth and entry into cell cycle
- MYB for CRC and breast cancer
- if you knock out Lop5 for MYB, then you have no MYB
- in cancer-prone mice, this let them survive longer, therefore MYB is necessary for tumourigenesis
- if you knock out Lop5 for MYB, then you have no MYB
- transcription factors vs receptor kinases
- Tumour Suppressor Genes
- Knudson's 2 hit model to completely lose TSG
- p53 = major transcription factor controlling several cellular pathways, including DNA repair and apoptosis
- induces apoptosis through PUMA, Noxa and BAX genes
- PUMA and Noxa -> Cyt C release and Bcl inhibition
- BAX -> cytochrome C release and caspase activation
- loss of p53 has greater effect on tumour growth compared to loss of PUMA, or other downstream components
- Knudson's 2 hit model to completely lose TSG
- p53 = major transcription factor controlling several cellular pathways, including DNA repair and apoptosis
- induces apoptosis through PUMA, Noxa and BAX genes
- PUMA and Noxa -> Cyt C release and Bcl inhibition
- BAX -> cytochrome C release and caspase activation
- loss of p53 has greater effect on tumour growth compared to loss of PUMA, or other downstream components
- to prevent tumour resistance to p53, nutlin binds with p53-inhibitor MDM2
- Bax/cyt C activation with Abt199 inhibition of Bcl2 inhibitors
- induces apoptosis through PUMA, Noxa and BAX genes
- to prevent tumour resistance to p53, nutlin binds with p53-inhibitor MDM2
- Bax/cyt C activation with Abt199 inhibition of Bcl2 inhibitors
- induces apoptosis through PUMA, Noxa and BAX genes
- gatekeeper genes - monitor cell cycle entry (p53, RB)
- caretaker genes - DNA repair (BRCA1 and BRCA2)
- Characteristics
- loss of differentiation
- disease of aging
- less inclined to stop growing, rather than growing faster
- Origin
- Support
- Cancer Associated Fibroblasts
- promoting tumour growth by acting as reservoir of growth factors and use paracrine signalling
- causes EMT
- allows chemotherapy resistance due to promotion of FAK signalling to avoid using BRAF, so that apoptosis is inhibited and allow continued growth (?)
- also CAF and ECM create protective shield around cancer cells
- factors produced depend on purpose
- TGF(b) to help tumour cell grow and recruit new cells, IL1 to modify immune response and collagen to set up the microenvironment
- MMP for space to grow, as well as for angiogenesis (VEGF)
- angiogenesis
- Tumour Associated Macrophages
- Macrophages recruited by CSF-1 chemotactic factors and matured into M2, by Il4
- produces MMP for angiogenesis, and EGF for general growth and division
- high production of IL6 and 8
- occurs by exisitng vasculature's growth into tumour OR chemotactic factors that draw cells in to create entirely new blood vessels
- HIF1 = transcritipn factor only stable at low oxygen, promote tumour division and growth
- Tumour Associated Macrophages
- angiogenesis
- Tumour Associated Macrophages
- Macrophages recruited by CSF-1 chemotactic factors and matured into M2, by Il4
- produces MMP for angiogenesis, and EGF for general growth and division
- high production of IL6 and 8
- Endothelial cells
- supplying nutrients and oxygen
- angiogenesis
- occurs by exisitng vasculature's growth into tumour OR chemotactic factors that draw cells in to create entirely new blood vessels
- HIF1 = transcritipn factor only stable at low oxygen, promote tumour division and growth
- Cancer Associated Fibroblasts
- Metastasis
- Invasion
- MMP secretion to break down ECM for movement towards vessel
- EMT to acquire mobile phenotype, assisted by CAF?
- environmental signals (TGF) promote EMT
- oncogenes, and epigentic changes allow movement and invasion
- Oncogenes
- Drive growth and entry into cell cycle
- MYB for CRC and breast cancer
- if you knock out Lop5 for MYB, then you have no MYB
- in cancer-prone mice, this let them survive longer, therefore MYB is necessary for tumourigenesis
- if you knock out Lop5 for MYB, then you have no MYB
- transcription factors vs receptor kinases
- Less E-cadherin and (b)-catenin
- More fibronectin and vimentin
- Oncogenes
- Intravasation
- triad formation with macrophages and endothelial cells to squeeze into blood vessel
- Circulation
- Tropism
- Seed and soil hypothesis: tumour cells prefer specific regions of body that accomodate its growth and expansion
- Mechanical circulation hypothesis: tumour cells follow the circulation to the next organ (e.g. gut to liver, breast to bone marrow and lungs, etc.)
- harsh environment with shearing forces and immune cells
- high % of cancer cells die in circulation
- travel in clusters ensures survival
- Tropism
- Extravasation
- tumour cells enhance "stickiness" at target region, platelets accumlulate angiopoietin-like protein 4 to open gaps in vessel walls
- platelets help tumour cells sto stop circulating and adhere to endothelial wall
- Survival
- high % die
- dormancy or colonisation
- epigenetic changes to allow MET and E-cadherin production
- requires: tumour-initiating properties, growth factors, angiogenesis
- Invasion
- Origin
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