8) Invasion and Metastasis

Question 1

What are the hallmarks of cancer?

Answer 1

Evading growth suppressors
Activating invasion and metastasis 
Replicative immortality 
Angiogenesis 
Resisting apoptosis 
Sustaining proliferative signalling

Question 2

Describe colon carcinogenesis:

Answer 2

1. Mutation in TS, adenomatous polyposis coli (APC)
2. Mutations blocking DNA repair genes = genomic instability
3. Oncogenes e.g. RAS
4. SMAD4 and p53 mutations

Question 3

Describe the route to metastasis, from primary tumour onwards:

Answer 3

Local invasion -> intravasation -> transport through vessels -> arrest in microvessels of various organs -> extravasation -> micrometastasis -> macrometastasis (colonisation)

Question 4

What cells are known to promote breast cancer metastasis? What mechanism allows this?

Answer 4

Tumour associated macrophages
Paracrine loop whereby tumour cells and macrophages use molecules (EGF and CSF-1) and receptors to stimulate growth and proliferation of each other

Question 5

What is necessary to allow movement of tumour cells?

Answer 5

Loss of epithelial cell to cell adhesion by repression of E-cadherin

Question 6

Describe adherens junctions:

Answer 6

Cadherins are dimers that span membrane and join cells together. Proteins in the cell bind to cadherin regulating its binding to actin, affects rigidity of cell

Question 7

What is loss of E-cadherin associated with?

Answer 7

Advanced tumour stage, tumour de-differentiaton, metastasis

Question 8

What activates epithelial to mesenchymal transition?

Answer 8

Different signalling pathways including TWIST, SNAIL (MAPK) and SIP1 that cause epithelial markers to be repressed and mesenchymal markers to be induced

Question 9

What is the collective migration mechanism?

Answer 9

Migration as a cluster of multicellular strand

Uses loss of cadherins and gap junctions

Question 10

What is the individual migration mechanism? (molecules required)

Answer 10

Ameoboid or single cells

Uses integrins and proteases

Question 11

Describe the process of mesenchymal migration:

Answer 11

Protrusion of membrane which then adheres to new part of surface. Translocation of cell using rho family. Then retraction of back of cell by dissolution of adhesions.

Question 12

What are focal adhesions?

Answer 12

Protein complexes through which the cytoskeleton of a cell connects to the ECM

Question 13

What are integrins?

Answer 13

Transmembrane receptors that are heterodimers made of alpha and beta subunits

Question 14

Describe how integrin signalling works:

Answer 14

Inside-outside bidirectional signalling
Ligand binding outside to integrin can induce effects in the cell
Inner signal can affect outside of cell by changes to cell adhesion

Question 15

Give examples of extracellular matrix degrading proteases:

Answer 15

Matrix metalloproteinases (MMPs)
Serine proteases
Bone morphogenic proteins

Question 16

Describe how angiogenesis is induced:

Answer 16

Tumours larger than 2mm need blood supply. Become hypoxic and cells secrete VEGF

Question 17

Give examples of cancer transport through body cavities (direct invasion):

Answer 17

Colon cancer to peritoneum
Lung cancer to pleura
Brain cancer to ventricles