Invasion And Metastasis Flashcards
What does metastasis require?
Cell adhesion Survival Proteolysis Migration Lymph-/angiogenesis Immune escape Homing to target organs
Describe E-cashed in in metastatic breast cancers
Most strong in physiology
Ca dependent, alpha-catenin linker proteins
Cadherin is active when nectin and cadherin are connected
Afadin- ponsin- vinculin
ADIP- alpha-actinin connects the two
Loss of E-cadherin leads to the most invasive lobular carcinomas- hyper methylation of promotor or MMP-induced shedding from the surface of breast cells
Loss of adherens lead to loss of intercellular adhesion and transcription activation leads to increased migration and invasiveness
p120 activates Rac and cdc42 And inhibits Rho to remodel the actin cytoskeleton
Release of beta-catenin partners with LEF goes to the nucleus to activate transcription of genes that help riot cells migrate
What is the importance of ECM interaction by tumour cells
Controlled by integrins and surface proteoglycans
Outside in signalling- binding to ECM changes conformation
Inside out signalling- binding of cytosolic domain to protein causes conformational changes
Talin binding to the beta subunit when in its open conformation is essential for integrin activation
Cell surface proteoglycans are receptors for laminins, collagen, hyaluronan- syndecan and CD44 family- highly glycosylated with heparan sulphate or chondroitin sulphate
The proteoglycans cross talk to activate (integrin) and localise (syndecan) p190RhoGAP-A to the membrane so it can inhibit RhoA and facilitate actin skeleton reconstruction
How do tumours overcome the mechanical barriers to invasion?
Basement membrane and the stromal environments
ECM degrading proteins- matrix metalloproteinases
Serine proteases activate these
They secrete MMP and stimulate stromal cells too
MMP degrade ECM, increase tumour cell migration and release latent growth and chemotactic factors
How do tumours home to their target organ
Selective growth
Selective adhesion to sites on the endothelial cells at the organ
Selective chemotaxis of circulating tumour cells to the organ producing soluble attraction factors
Invasion of the endothelium- rolling via weak E/P-selectin - CD44, CEA, PODXL then string ICAM1, VCAM1- integrins the extravasation
Or platelet mediated capture followed by growth
Selectins tigger biochemical signals that ultimately stop rolling of tumour cells over the endothelium➡️ increase chemokine production➡️ production of MMP➡️ tumour invasion, out of vasculature
What is cell invasion?
Process related to cell migration which defines the ability of the cells to navigate through their own tissue or infiltrate neighbouring tissue- an invasive phenotype is essential for metastasis
