Metastasis

Question 1

briefly describe the stages of metastasis

Answer 1

invasion, intravasion, survival in circulation, adaptation to a new environment

Question 2

describe the linear model for metastasis

Answer 2

primary tumour undergoes successive rounds of mutation and selection for metastatic cells within the heterogenous population

Question 3

what is the evidence for the linear model of metastasis

Answer 3

there is direct correlation between the size of the primary tumour and metastatic events

Question 4

describe the parallel model for metastasis

Answer 4

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

Question 5

what are the 3 metastatic initiation genes and what is their role

Answer 5

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

Question 6

what is the result of overexpression of metastatic initiation genes in epithelial cells

Answer 6

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

Question 7

what is the role of metastatic progression genes

Answer 7

help the motile cells break into and out of the blood stream to colonise secondary environment

Question 8

what are the 4 metastatic progression genes

Answer 8

EREG, PTGS2, ANGPTL4 and LOXP

Question 9

what is the role of EREG in metastatic progression

Answer 9

it is necessary to break down endothelial barriers

Question 10

what is the role of PTGS2 in metastatic progression

Answer 10

increases the ability of cancer cells to pass through endothelial barriers

Question 11

what is the role of ANGPTL4 in metastatic progression

Answer 11

dissociates vascular endothelial cell-cell junctions in particular adherin junctions

Question 12

what is the role of LOXP in metastatic progression

Answer 12

acts on extracellular matrix proteins to establish the microenvironemtn for cancer cells

Question 13

which genes are required for colonisation

Answer 13

virulence genes

Question 14

how long does it take for cells to acquire virulence genes

Answer 14

sometimes years but in other cases quite quickly

Question 15

which virulence genes are required in lung metastasis

Answer 15

ID1 and ID3

Question 16

what is thought to be the virulence gene present in breast cancers which metastasise to colonise bone

Answer 16

parathyroid hormone related protein (PTHRP)

Question 17

what is the result of tumour cells which have become highly motile and colonised but don’t have virulence genes to grow further

Answer 17

metastatic dormancy/ micrometastasis

Question 18

how do tumour associated macrophages in the tumour microevnvironment aid local invasion

Answer 18

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)

Question 19

how do cancer associated fibroblasts aid metastasis

Answer 19

help in breaking through blood vessels, matrix remodelling and angiogenesis

Question 20

what are potential therapeutic interventions for metastasis

Answer 20

targeting dormant metastasis or interfering with the tumour microenvironement

Question 21

how does the antibody based therapy called denosumab prevent bone metastasis

Answer 21

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

Question 22

how do bisphosphonates inhibit bond metastasis

Answer 22

inhibit attachment of tumour cell to broken bits of bone (currently in clinical trials