Metastasis Flashcards
briefly describe the stages of metastasis
invasion, intravasion, survival in circulation, adaptation to a new environment
describe the linear model for metastasis
primary tumour undergoes successive rounds of mutation and selection for metastatic cells within the heterogenous population
what is the evidence for the linear model of metastasis
there is direct correlation between the size of the primary tumour and metastatic events
describe the parallel model for metastasis
tumour cells may disseminate very early in malignant progression and colonise multiple secondary sites. after a long period of time these acquire mutations independently of the primary tumour
what are the 3 metastatic initiation genes and what is their role
snail twist and slug- transcription factors which regulate EMT transition, break up cells, break up adhesion molecules and cause a change in the cells actin skeleton
what is the result of overexpression of metastatic initiation genes in epithelial cells
proteins in epithelial cells switch to mesenchymal type and undergo morphology alterations to become stretched out- epithelial mesenchymal transition (EMT). this breaks adhesion junctions and cells become highly aggressive expressing enzymes which break barriers and so become highly motile
what is the role of metastatic progression genes
help the motile cells break into and out of the blood stream to colonise secondary environment
what are the 4 metastatic progression genes
EREG, PTGS2, ANGPTL4 and LOXP
what is the role of EREG in metastatic progression
it is necessary to break down endothelial barriers
what is the role of PTGS2 in metastatic progression
increases the ability of cancer cells to pass through endothelial barriers
what is the role of ANGPTL4 in metastatic progression
dissociates vascular endothelial cell-cell junctions in particular adherin junctions
what is the role of LOXP in metastatic progression
acts on extracellular matrix proteins to establish the microenvironemtn for cancer cells
which genes are required for colonisation
virulence genes
how long does it take for cells to acquire virulence genes
sometimes years but in other cases quite quickly
which virulence genes are required in lung metastasis
ID1 and ID3
what is thought to be the virulence gene present in breast cancers which metastasise to colonise bone
parathyroid hormone related protein (PTHRP)
what is the result of tumour cells which have become highly motile and colonised but don’t have virulence genes to grow further
metastatic dormancy/ micrometastasis
how do tumour associated macrophages in the tumour microevnvironment aid local invasion
express metalloproteinases and cysteine cathepsin proteases to allow cells to enter blood stream as well as breaking down the matrix to allow space for tumour growth (matrix remodelling)
how do cancer associated fibroblasts aid metastasis
help in breaking through blood vessels, matrix remodelling and angiogenesis
what are potential therapeutic interventions for metastasis
targeting dormant metastasis or interfering with the tumour microenvironement
how does the antibody based therapy called denosumab prevent bone metastasis
it interferes with RANK-L which is unregulated in bone metastasis and activates osteoclast which causes a hole in the bone to create room for the tumour
how do bisphosphonates inhibit bond metastasis
inhibit attachment of tumour cell to broken bits of bone (currently in clinical trials
