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Cancer - Hallmarks - Coggle Diagram
Cancer - Hallmarks
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- Sustaining Proliferation Signalling
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- Proto-oncogenes encode :
Growth factors GF
GFRs
Signal transducers
TFs
Cell cycle components
- Oncogenes are created by mutations in proto oncogenes
- Oncogenes encode oncoproteins that promote cell growth in absence of normal growth promoting signals
- Oncoprotein activity does not depend on external signalling
- Cells expressing oncoproteins are free from normal checkpoints and controls that limit growth
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Autophagy
Consumption of the body’s own tissue as a metabolic process occurring in starvation and certain diseases
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Nutrient starvation, radiotherapy, cytotic drugs can induces elevated autuphagy
Protects cancer cells via resistance to apoptosis
Necrosis
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Inflammatory cells can be tumour promoting
- Angiogenesis
- Cancer cell proliferation
- Invasiveness
- Growth stimulating factors
Release Bioactive regulatory factors - IL-1α
Stimulate neighbouring cells to proliferate
Facilitate neoplastic progression
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- Newly formed endothelial cells secret GFs such as IGFs and PDGF (platelet derived growth factor)
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- Hypoxia triggers angiogenesis by actions of HIF-1a on the transcription of VEGF (Vascular endothelial growth factor)
- p53 induces synthesis of angiogenesis inhibitor thrombospondin-1
- RAS, MYC, MAPK signalling upregulate VEGF expression
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- Evading Immune Destruction
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- Failure to produce tumour antigens
- Loss or reduced expression of MHC molecules.
- Activation of immunoregulatory pathways.
- Secretion of immunosuppressive factors by cancer cells (TGFb) –inhibits T cell activation
- Enabling Replicative Immortality
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- Activating Invasion and Metastasis
Phase 1
Invasion of ECM
- Loosening of cell-cell contacts
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- Attachment to novel ECM components
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- Migration of tumour cells
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Phase 2
Vascular dissemination, homing of tumour cells and colonisation
Spread through
- Seeding of body cavities and surfaces
- Lymphatic spread
- Haematogenous spread
Aim
- Emerge from primary mass
- Enter blood vessel / lymphatics
- Produce secondary growth
Metastatic Cascade
- Invasion and passage of through basement membrane
- Migration through extracellular matrix
- Migration into the vessels [Intravasation]
- Formation of tumour cell emboli
- Adhesion to basement membrane
- Extravasation through vessels
- Formation of metastatic tumour
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Hallmarks
Definition
Essential alterations in cell physiology that collectively lead to malignant growth of a normal cell
8 Hallmarks
- Sustaining proliferative signalling
- Evading growth suppressors
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- Enabling replicative immortality
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- Activating invasion and metastasis
Emerging:
- Reprogramming of energy metabolism
- Evading immune destruction
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Tumour Microenvironment
Normal cells contribute to the acquisition of hallmark traits by creating the tumour microenvironment
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- Evading Growth Suppressors
Mutated, inactivated Tumour Suppressor Genes allows evasion of cell cycle regulatory checkpoints
RB (Retinoblastoma)
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Inhibition of RB
Anti-proliferation Effect Lost due to:
Loss of function mutations affecting RB
Gene amplification of CDK4 and Cyclin D genes
Loss of cyclin-dependant kinase inhibitors (p16/INK4a)
Viral oncoproteins that bind RB (E7 HPV protein)
TP53
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p53 Regulates cell progression, DNA repair, cellular sequences and apoptosis
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- Reprogramming of Energy Metabolism - Warburg Effect
Metabolic Reprogramming of Cancer cells, by upregulation of aerobic glycolysis
- Oncogeneic mutations involving growth factor signalling pathways + other factors such as MYCd, dyregulate metabolic pathways
- High Glucose intake
- Increased conversion of glucose to lactose (glycolytic pathway)
- Provides rapidly diving tumour cells with metabolic intermediates - needed for synthesis of cellualr components
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