MECHANISM OF DISEASE Flashcards
What does 5 fluorouracil do?
Prevent synthesis of thymidine
What does cisplatin do?
Bind to DNA cause damage and block repair
What does vinca alkaloids do?
Stabilise free tubulin, prevent microtubule polymerisation
What does paclitaxel do?
Stabilise microtubules, prevent de-polymerisation and arrest cell mitosis
Describe the steps of necrosis
- Result of an injurious agent or event – whole groups of cells are affected
- Initial events are reversible, later ones are not
- Lack of O2 – prevent ATP production
- Cells swell due to influx of water – ATP required for ion pumps to work
- Lysosomes rupture – enzymes degrade other organelles and nuclear material haphazardly
- Cellular debris released, triggering inflammation
What are the cytoplasmic changes in necrosis
- Opacification – protein denaturation and aggregation
2. Complete digestion of cells by enzymes causing cells to liquify
What are the biochemical changes in necrosis
- Releases enzymes – Creatine kinase or lactate dehydrogenase (into extracellular enviro.)
- Release of other proteins such as myoglobin – useful to measure extent of damage
Describe the steps in apoptosis
- Programmed cell death of one or a few cells
- Events are irreversible and energy (ATP) dependent
- Cells shrink as the cytoskeleton is disassembled
- Orderly packaging or organelles and nuclear fragments into membrane bound vesicles
- New molecules are expressed on vesicles membranes that stimulate phagocytosis without causing an inflammatory response
Cytoplasmic changes in apoptosis
- Cell shrinks. Organelles packaged into membrane vesicles
- Cell fragmentation. Membrane bound vesicles bud off
- Phagocytosis of cell fragments by macrophages and adjacent cells
- No leakage of cytosolic components
Nuclear changes in apoptosis
- Nuclear chromatin condenses on nuclear membrane
2. DNA cleavage
Biochemical changes in apoptosis
- Expression of charged sugar molecules on outer surface of cell membranes (recognised by macrophages to enhance phagocytosis
- Protein cleavage by proteases, caspases
Caspase activation
Inactive procaspase Y cleaved
Caspase X + prodomain
Caspase X activates caspase Y
TNF extrinsic apoptosis method
- TNF binds to TNFR bringing death domains close together
- Environment for dimerisation with other proteins like FADD
- Increases the concentration of death effector domain which recruits procaspase 8. Structure = DISC
- Activate - autoproteolysis. Becomes caspase 8
what is cancer?
Group of diseases characterised by:
abnormal cell proliferation
tumour formation
invasion of neighbouring normal tissue - able to supply themselves with nutrients
Metastasis to form new tumours at distant sites
Evidence suggesting cancer is a disease of the genome at the cellular level
carcinogens alter DNA = mutations - overtime it’ll accumulate.
Accumulation occurs after cells defence mechanisms of DNA repair has been evaded.
Mechanisms block carcinogenesis - but burdening system = higher chance cell escape surveillance
What is an oncogene
proto-oncogene
mutated = signals that cause uncontrolled growth
The 5 models of carcinogens
- Mutational
- genome instability
- non genotoxic
- darwinian
- tissue organisation
What is Ataxia telangiectasia
Neuromotor dysfunction - dilation of blood vessels, spider veins.
Mutation in ATM gene - codes serine/threonine kinase - recruited and activated by dsDNA breaks = cell cycle arrest
What is Bloom’s syndrome
Mutation in BLM gene - instructions coding a member of RecQ helicase family - maintain structure and integrity of DNA
Symptoms = short stature, skin rash develop after exposure to the sun
What is Lynch type
no symptoms - 1st sign = symptoms of bowel and womb cancer
Mutation in DNA mismatch repair genes - MLH1 and MSH2
Key steps in cancer progression
- Transformation - extensive mutagenic and epigenetic changes followed by colonal selection
- Angiogenesis - new blood vessel formation - overcome limitations - hypoxia
- Motility and invasion - epithelial cells into mesenchymal transition
- Metastasis - colonisation of target organs - ability to expand from micro metastases
Angiogenesis vs vasculogenesis
Angiogenesis = formaiton of new blood vessels from pre-existing vessels Vasculogenesis = formation new blood vessels from progenitors
Type of angiogenesis
Developmental/vasculogenesis = organ growth
Normal angiogenesis = wound repair, placenta during pregnancy, cycling ovary
Pathological angiogenesis = tumour angiogenesis, ocular and inflammatory disorders
Tumour angiogenesis mechanism
- small tumour = oxygen and nutrients from capillaries become limiting
- tumour switches on expression of angiogenic genes/factors = new blood vessel growth
- New network of blood vessels grow in and around tumour = increase oxygen and nutrients = growth and route to shed off and spread
How does Vascular endothelial growth factor work
- VEGF bind to VEGF-R2 on endothelial cells
- VEGF/VEGF-R2 dimerise at plasma membrane and recruit cofactor
- Activate 3 major signal transduction pathways - phospholipase C, PKB, Ras/Raf Mek
- VEGF activate cell survival, vascular permeability, gene expression and cell proliferation
Mechanisms of tumour cell motility
Increase mechanical pressure - rapid cellular proliferation
Increase motility of malignant cells – epithelial into mesenchymal transition
Increase production of degradative enzyme by both tumour cells and stromal cells
Urokinase type plasminogen activator
Pro-uPA bind to uPA receptor = active uPA = activate plasminogen to plasmin = matrix metalloproteases
Function of matrix metalloproteinases
Permit invasion by extracellular matrix and release matrix bound angiogenic factors
Notochord
Rod of cells secretes extracellular molecules - instruct the ectoderm on top of it to be neural tissue
