People and illness Week 2 Flashcards
Describe the 7 steps in the metastatic cascade:
- Local invasion
- Neovascularisation/angiogenesis
- Detachment
- Intravasation
- Transport in blood or lymph
- Lodgement/arrest
- Growth at ectopic site
Describe the 7 steps of metastases:
- Reduced cell to cell adhesion = E.caadherin
- Altered cell to substratum adhesion = Integrins
- Increased motility = HGF
- Increased proteolytic ability = serine proteases and MMP’s
- Angiogenesis = VEGF
- Intra/extravasation = acting like WBC’s
- Proliferation in local/ectopic environments = TME (tumour microenvironment)
Describe step 1 = Reduced cell to cell adhesion = E-cadherin
- e-cadherins are proteins that form zips at cells adherens junctions
- e-cadherins bind to alpha/beta catenin molecules inside cells which are attached to the actin/myosin cytoskeleton
- Calcium is needed to e-cad molecules to bind
- the higher a tumour grade, the less e-cad binding there is between the tumour cells
- in some carcinoma cells, e-cad promoter genes have been inactivated
- metatasis occurs when:
1. Mutations in e-cad
2. Mutations in interacting proteins e.g. B-catenin
3. Mutations in the transcription factors that switch E-cad on/off
Describe step 2 = Altered cell to substratum adhesion = Integrins
- integrins are cell adhesions molecules found on plasma membranes of cells that bind to extracellular matrix molecules
- they are heterodimers (made of 24 combinations of alpha/beta subunits)
- integrins can be expressed on tumour cells
- they allow attachment/detachment points and cells can be motile, are found in hemi/desmosomes
- metastasis occurs when:
1. reduced integrin binding to BM
2. increased cell motility and migration through stroma
3. increased cell adhesion to blood vessels
4. integrins can provide binding points on cell membranes for proteolytic enzymes to work
Describe step 3 = Increased motility = HGF
- hepatocyte growth factor (HGF) = scatter factor = induces epithelial cells to dissociate and migrate and become invasive
- it is a mitogen (GF), morphogen (developmental role) and motogen (motility factor)
- produced by stroma cells within the microenvironment
- C-met is an RTK on tumour cells
- C-met on tumour cell epithelium can bind to HGF on stromal cells and this causes increased phosphorylation of B-catenin molecules in the cell and causes disrupted e-cad adhesion
Describe step 4 = Increased proteolytic ability = serine proteases and MMP’s
SERINE PROTEASES:
- secreted by cell in tumour microenvironment and bind to receptors on tumour cell to help them move about
MMP’s: e.g. collagenases, stromelysins - (MMP3)
- produced by white blood cells
- involved in tissue and wound repair
- secreted as zymogens and tightly regulated as transcription factors
- MMP’s structurally similar to integrins -> MMP’s can bind to integrin receptors and allow tumour cells to be picked up and transported through stroma
Metastasis occurs when:
- tumour cells stimulate stromal cells to make MMP’s
- tumour cells can then bind to MMP’s through integrin receptors -> allowing tumour to break away and invade other body areas
Describe step 5 = Angiogenesis = VEGF
- cells in necrotic core make HIF (hypoxia induceable factor)
- HIF causes tumour cells to make VEGF
- VEGF picks up epithelial cells with the VEGF receptor in the stroma
- coagulation occurs around the tumour and a fibrin clot forms
- fibrin clot = net that vascular endothelial cells can bind to and migrate on and start dividing on
- endothelial cells can bind to MMP’s/integrins and move through the stroma to reach this fibrin net and then form new blood vessels which supply the tumour
Describe step 6 = Intra/extravasation = acting like WBC’s
- cells that are metastasising copy the properties of other cells that migrate in the body e.g. WBC’s
1) rolling adhesion: specific receptors on metastasising cells bind to selectin on endothelial cells
2) tight binding: integrins on metastasising cells bind to ICAM’s on endothelial cells
3) diapedesis when adhesions between cells weaken and cancer cells can move through and spread
4) migration then occurs due to attraction by chemokines or other factors in the TME
Describe step 7 = Proliferation in local/ectopic environments = TME (tumour microenvironment)
- there are various cells in a TME that include fibroblasts, pericytes and they may secrete GF’s, chemokines and enzymes
- these cells and chemicals can work for/against the tumour to stop/aid metastasis
1) seed-soil hypothesis: tumour cell is seed and TME is soil, both must be compatible for growth
2) mechanical hypothesis: due to vascular and lymph pathways tumour cells will naturally be picked up and spread in a certain way
Which drug blocks VEGF binding and tries to stop tumour metastasis by preventing the growth of new blood vessels?
Avastin (bevacizumab) = a monoclonal antibody
What is BRAF and its normal function?
- a human oncogene that encodes for the protein B-RAF
- member of the MAP-kinase pathway
- BRAF mutations seen in 60-70% melanomas
Describe the MAP kinase pathway and the involvement of BRAF in this:
1 - ligand binds to portion of RTK outside the membrane
2 - dimerisation and autophosphorylation of tyrosine portions of the RTK
3 - GRB2 (growth factor receptor bound protein 2) can bind to RTK and be phosphorylated
4 - various other secondary messengers are then activated (SOS) and eventually RAS is activated
5 - RAS activation involves change of bound GDP -> GTP
6 - Once activated, RAS can bind to other effector proteins and activate them (BRAF)
- BRAF phosphorylates and activates MEK
MEK then activates ERK (extracellular signal regulated kinases) by phosphorylation
- eventually nuclear transcription and gene expression can occur
- cell proliferation is stimulated
- normally BRAF- RAS-GTP complex is inactivated shortly after activation to stop continuous stimulation of MAP-K pathway and to stop uncontrolled cell proliferation
Describe how the MAP-kinase pathway is disrupted when there is a BRAF mutation:
- in the mutation the BRAF-RAS-GTP complex is not inactivated and BRAF continues to activate and phosphorylate proteins downstream in the MAP-kinase cascade and there is continual uncontrolled cell proliferation
What is vemurafinib? (vem-yoo-raf-enib)
- causes programmed cell death in melanoma cell lines
- only effective in the V600 BRAF mutation where the amino acid at position 600 which is normally valine, has been replaced by glutamic acid
- vemurafinib is a BRAF inhibitor and binds to the ATP binding sites of BRAF to slow cell growth and shrink tumours
SIDE EFFECTS: - sensitivity to sun
- vomiting
- headaches
- tired
- hair thinning
- taste changes
- constipation
- liver changes
How does normal immune surveillance of cancer work throughout our bodies?
3 phases of immune surveillance:
1) Elimination - body attacks and destroys any abnormal cells, uses innate (NK, phagocytes, dendritic cells) and adaptive (T and B lymphoytes, APC’s) to do this
2) Equilibrium - when tumours are unstable and fast growing, tumours are struggling to be kept under control by the body and are not being completely eradicated
IMMUNOEDITING OCCURS allowing the tumoutrs to start to thrive:
- loss of expression of specific antigens on tumour surface so they hide and an immune response cannot be mounted against them
- tumour cells stimulate host cells to make MMP’s which they can bind to and migrate about
- tumours express molecules to attract T-regulatory cells which switch off genes that produce protective factors in the cell cycle and allow cell proliferation
3) Escape - tumour evades normal immune control and clinical cancer develops with large uncontrolled tumours that undergo metastasis
- there are too many tumour cells for NK cells and cytotoxic T-lymphocytes to handle
What are the two branches of immunotherapy that can be used in to treat cancer and how do they work?
1) Non-cellular therapies (passive therapies) harness immune system components like cytokines and antibodies
2) Cellular = target specific cells in the body e.g. T-cells, stem cells
Describe the 9 non-cellular therapies, briefly describing how each works:
1) Cytokine therapy with interferons, IF type 1 are good for chronic myeloid leukaemia and make cancers more visible to the immune system by up-regulating MHC class 1 expression, multiple dosing needed and have flu like symptoms
2) IL-2 causes T-cells to grow and proliferate and attack the cancer, can also attach poison onto IL2 molecule so that certain cancers which have IL2 receptor will also be killed by the poison when they bind IL2
3) Bacteria injection = causes big inflammatory immune response
4) TLR- mediated immunity = TLR’s are found on IMMUNE cells and recognise PAMP’s on pathogens and cancerous cells. Can use drugs which are TLR’s to increase the innate response to infection
5) Vaccines - against certain proteins in the cancer e.g. HPV
6) Monoclonal antibodies - made against antigen on cancer, antigens on molecules in the TME needed for the cancer to survive, or antigens on receptors that are inhibiting the immune system and allowing cancers to thrive e.g. bevacizumab
7) PD inhibitors - healthy cells express PDL1 (programmed death ligand 1) to tell the immune system not to attack as they are good cells and the PDL1 binds to PD1 receptors on T cells = the T cells know not to attack. Make antibodies to block PD1 on T cells so that T cells destroy everything, or make PDL1 blockers so that T cells cannot recognise healthy or bad cells
8) Checkpoint inhibitors - when healthy cell binds to a T-cell, it tells the T cell to make CLTA4 = checkpoint molecule that switches off T cell. Tumour cells can tell T-cells to make CTLA4 and switch them off. Anti-CTLA4 drugs boost T-cell activity
9) BITE: bi-specific T-cell engagers = ‘glue’ = take an antibody that binds to receptor on T cells and stick it to an antibody that binds to receptor on tumour cells
Describe the two main cellular therapies used:
1) Engineering T cells: T-cells made with tumour receptor attached to them, issues as receptor can be too general and adverse effects caused in the body
2) Stem cell therapies: use of autogenic (self) or allogenic (from someone else)
- stem cells collected from bone marrow
- tumour cells killed off with radio/chemotherapy
- stem cells re-implanted and cause components of the immune system to reform and healthy new leukocytes are made to replace the cancerous ones and replenish the immune system
What is depression and describe clinical features?
3 core features
- low mood
- anhedonia
- low energy
- cognitive features: slow thought, suicidal thoughts, poor concentration and attention
- biological symptoms: disturbed sleep, low appetite, low libido, low energy, constipation, amenorrhoea
- psychotic symptoms: delusions, hallucinations
What factors are involved in causing/maintaining depression?
1) Biological - genetics
2) Psychological - behavioural, cognition distortions (maximisation of bad things, minimisation of good things)
3) Social - predisposing factors (family had it), precipitating factors (death)
- neurochemical theories with dopamine, serotonin and noradrenaline imbalances
- neuroendocrine theories with hypo -> pituitary -> adrenal/thyroid axis dysfunction
What are the treatment options available for depression?
1) Biological - various drugs (see other card)
2) Psychological - behavioural therapy where goals are set, CBT where you keep a diary, psychodynamic psychotherapy where you review the past with an aim to change the future
3) Social - housing, finances, family, relationship councelling
What is psychotic depression?
Depression + delusions/hallucinations
How do you diagnose depression?
ILD diagnosis criteria = 1 of the 3 defining features present every day for 2 weeks (only for one week of psychotic symptoms are also present)
How do you diagnose depression?
ILD diagnosis criteria = 1 of the 3 defining features present every day for 2 weeks (only for one week of psychotic symptoms are also present)
- good history
- blood tests (anaemia/thyroid issues)
- other medication causes (OCP)
- CT scan
Describe 5 drugs types that can be used to treat depression, name one and briefly how each works:
1) SSRI’s = sertraline = selective serotonin re-uptake inhibitors = more serotonin in synapses
2) Tricyclic antidepressants = amytryptiline => increase NA and serotonin and reduce ACh to restore balance
3) SNRI’s = venlaflaxine
4) NASSA’s (noradrenergic and specific serotonergic antidepressants) = mirtazepine
5) NARI’s (noradrenergic reuptake inhibitors) = roboxetine
- all have side effects of nausea, vomiting, weight gain, sweating
What are the effects of noradrenaline?
Stress
What are the effects of serotonin?
Sleep, eat, sexual drive and mood
