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40 Cards in this Set
- Front
- Back
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metastasis
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process by which tumours disseminate to distant sites to establish secondary tumours
HALLMALK of MALIGNANT TUMOURS |
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metastasis mechanism
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cells become disorganised->proliferation
Detach from original location (breach BM) Migrate through stroma cross EC layer travel through blood/lymph vessel extravasate into distinct tissue (lymph -> nodes, blood->anywhere) establish a new colony (characteristics of primary tiddue) |
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Genomic instability
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allows mutations necessary for each step of migration
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cellular changes for migration/survival in stroma
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altered cell-cell adhesion
altered cell-ECM adhesion altered polarity altered MMP expression |
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Some cancer cells are ______ by normal cells
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extruded
e.g increased Erb2/Ras -> Basal extrusion e.g Src/Ras -> apical extrusion |
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experiment to determine extrusion of cancer cells
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mammary gland cells -> acini
induce oncogene expression in one cell only (after 17 days) |
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If second step is needed, what is it
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MMP expression
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E-cadherin
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mediates cell-cell adhesion
(+desmoplakin) |
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loss of E-cadherin via
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TFs
degredation phosphorylation gene hypermethylation mutation OFTEN LOST IN CANCER NEEDED FOR METASTASIS |
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inhibition of cell-cell contacts in pre-malignant cells
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-> MIGRATION
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Addition of E-cadherin to cancer cells
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-> NON-MALIGNANT (can not metastasise)
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In T-antigen transformed (adenocarcinoma) mice
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when crossed with Rad1-E-cadherin
lower incidence of carcinoma - NONE with E-cadherin |
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TIMPs
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Tissue Inhibitors of Metalloproteinases
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Tumours express MMPs and glycosidase
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degrade ECM
release GFs |
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integrins
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attach to ECM
altered in malignancy |
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integrin function
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migration
survival proliferation cellular differentiation |
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Targeting integrins in cancer
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integrins bind RGD sequence in ECM proteins (fibronectin)
decoy RGD tripeptide reduces malignancy |
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Rock activation
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-> intracellular tension
via LEM-kinase activation -> actin assembly via myosin-II phosphatase -> myosin II ATPase -> MORE COLLEGEN CROSSLINKING ACTIVATED IN CANCER |
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Increased ECM stiffness
-> _____ _____ -> FAK activation -> ____ ______ ______ |
integrin coupling
beta catenin activation |
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FAK
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Focal Adhesion Kinase
ACTIVATED IN CANCER |
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Focal adhesions
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contain integrins
bind cell to ECM |
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Actin polymerisation
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protrudes lamellipodium at plus end
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myosin II
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contracts cell (at the back)
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Cell movement driven by
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SMALL GTPASES
Rac-> Lamellipodium Cdc42 -> Filopodium Rho -> Stress fibre formation |
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ErbB2/B3 activates migration via
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Memo
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ErbB has _ autophosphorylation sites
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5
mutate all -/migration |
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sites _/_ --> migration
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C/D
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Memo binds
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p-D
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______ ______ of locomotion is overcome by cancer cells
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CONTACT INHIBITION
normally fibroblasts -/ cell migration cancer cells have increased RTKs (Ephrin receptors) -> MIGRATE |
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cells migrate together
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PIONEER cell at front
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MMPs
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degrade collegen in stroma
e.g MT1-MMP |
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cells pull on matrix via
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integrins/stress fibres
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cell-cell adhesion mediated by
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N-cadherin being switched on
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cytoskeleton generates tension
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drives migration
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For metastasis cells must
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survive sheer stress
attach to new vessel in target organ extravasate |
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Metastatic site depends on
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Micrometastases
simple blood flow (to next capillary bed) Seed & soil (site chemically similar to primary site) |
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seed and soil
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some tissues DON'T get metastases (e.g cartilidge)
prostate -> bone melanoma -> lung |
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chemokines
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drive homing response - bind to specific chmokine receptors on cancer cells
different in different areas of vasculature ->seed & soil |
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Metastasis due to
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accumulated selection
metastatic variants both |
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Self-seeding
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multidirectional capacity of cancer cells to seed distant organs as well as self-seed a primary tumor
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