Invasion and Metastasis

Question 1

How are tumours grouped into different types?

Answer 1

By their tissue of origin

Question 2

What is the name for benign and malignant tumours arising from the epithelium?

Answer 2

Adenoma/Papilloma and Carcinoma

Question 3

What is the name for benign and malignant tumours arising from connective tissue?

Answer 3

Lipoma/Fibroma/Haemangioma and Sarcoma

Question 4

What is the name for benign and malignant tumours arising from lymphoid tissue?

Answer 4

Lymphoid hyperplasia and Lymphoma

Question 5

What is the name for benign and malignant tumours arising from haemopoietic tissue?

Answer 5

Myeloid proliferations and Leukaemia

Question 6

What is the name for benign and malignant tumours arising from germ cells?

Answer 6

Terratoma and Germinoma

Question 7

How is benign large colon adenoma seen macroscopically?

Answer 7

Polyps

Question 8

What is a prerequisite to the metastatic cascade?

Answer 8

Accumulation of genetic mutations

Question 9

Which hallmarks of cancer are important for metastatic disease?

Answer 9

• Inducing angiogenesis

- Activating invasion and metastasis

Question 10

What happens in growth and invasion?

Answer 10

Primary tumour forms and invades tissues locally.

Question 11

What happens in transport to distant sites?

Answer 11

Intravasation, transport through the circulation and arrest in microvessels of various organs

Question 12

What happens for metastasis to thrive at a new site?

Answer 12

Extravasation into new tissue, formation of micrometastasis, and colonisation of a macrometastasis

Question 13

What does metatstasis require?

Answer 13

Environmental changes

Question 14

What is detected in stroma surrounding many human cancers?

Answer 14

Tumour associated macrophages

Question 15

What does a lack of ability to express tumour associated macrophages correlate with?

Answer 15

Decreased risk of developing metastsis.

Question 16

How do tumour cells and macrophages support each other in cell migration of mammary tumours?

Answer 16

Macrohoages express EGF which acts on the EGF receptor of tumour cells. Tumour cells then express CSF-1 which works on the CSF-1 receptor in the macrophage.

Question 17

What needs to be disrupted in order for cell migration to occur?

Answer 17

Cell-cell adhesions

Question 18

What is epithelial-mesenchymal transition?

Answer 18

EMT = when structure of cells goes from strong cell-cell adhesions and interactions to more like mesenchyme cells in phenotype

Question 19

What cell-cell interactions are disrupted?

Answer 19

• Tight junctions
• Adherens junction
• Desmosomes

Question 20

What is an adherens junction?

Answer 20

Junction formed by 2 cadherin molecules which span the extracellular membrane of both cells.

Question 21

What is the adherens junction regulated by?

Answer 21

Ca2+

Question 22

What happens on the intracellular side of the cadherin?

Answer 22

Many proteins can bind to it to help regulate its function and confer more structure and stability to keep the cell rigid

Question 23

What change in E-cadherin expression is associated with aggressive bladder cancer?

Answer 23

Aberrant or (-) - advanced tumour stage, tumour de-differentiation, lymph node metastasis and increased risk of death.

Question 24

What is EMT activated by?

Answer 24

Different signalling pathways, producing Twist, Snail and SIP1.

Question 25

What do the EMT pathways result in?

Answer 25

Inhibition of E-cadherin expression, and induction of mesenchymal marker expression

Question 26

How many migration strategies are there?

Answer 26

4

Question 27

Name the migration strategies

Answer 27

- Ameoboid - Mesenchymal (single cells/chains) - Cluster/cohorts - Multicllular strands/sheets

Question 28

Which tumour types migrate via the ameoboid strategy?

Answer 28

- Lymphoma - Leukaemia - SCLC

Question 29

Which tumour types migrate via the mesenchymal strategy?

Answer 29

- Fibrocarcinoma - Glioblastoma - Anaplastic tumours

Question 30

Which tumour types migrate via the cluster/cohort strategy?

Answer 30

- Epithelial cancer | - Melanoma

Question 31

Which tumour types migrate via the multicellular strand/sheet strategy?

Answer 31

- Epithelial cancer | - Vascular tumours

Question 32

What are the 4 steps in mesenchymal migration?

Answer 32

- Protrusion - Adhesion - Translocation - Retraction

Question 33

What happens in protrusion?

Answer 33

Polymerised actin pushes the membrane at the leading edge in the direction of movement driven by key Rho family GTPases

Question 34

What happens in adhesion?

Answer 34

Cell forms new contacts close to the leading edge using a Rho family GTPase

Question 35

What happens in translocation?

Answer 35

Acto-myosin contraction promotes translocation of the cell body using a Rho family GTPase

Question 36

What happens in retraction?

Answer 36

Loss of adhesions in tail end of cell and tail retraction

Question 37

What underpins mesenchymal migration?

Answer 37

Integrin signalling

Question 38

What are integrins?

Answer 38

Transmembrane receptors that attach the cell cytoskeleton to the ECM - made of an alpha and beta subunit. 24 heterodimers (18a and 8b)- and mediate focal adhesions

Question 39

Which direction do integrins signal in?

Answer 39

Both into and out of the cell

Question 40

Why do invading cancer cells have to have a proteolytic function?

Answer 40

So they can move through and degrade the ECM

Question 41

Name some ECM Degrading Proteases

Answer 41

- Matrix metalloproteinases (MMPs) - Serine proteases - Adamalysin-Related Membrane proteases - Bone-morphogenic protein -1 type metalloproteases - Heparanases - Cysteine proteases

Question 42

What is angiogenesis?

Answer 42

New blood vessel formation

Question 43

What induced angiogenesis in tumours?

Answer 43

Hypoxia

Question 44

What is the mechanism fro hypoxia-induced tumour angiogenesis?

Answer 44

Tumour larger than 2mm requires more blood vessels. Endothelial cells release paracrine growth factors. Tumour cells secrete VEGF.

Question 45

What is sometimes seen within a tumour?

Answer 45

High levels of necrosis in the centre of large tumours

Question 46

What can transport cancer cells to distant sites?

Answer 46

- Blood vessels - Lymphatics - Body cavities via direct invasion

Question 47

Why can cancer cells move via lymphatics?

Answer 47

No basement membrane

Question 48

Give some examples of transport to distant sites via body cavities

Answer 48

- Colon cancer to peritoneum - Lung cancer to pleurae - Brain cancer to ventricles

Question 49

What are the steps that take a CTC to extravasation?

Answer 49

Capture -> Rolling -> Arrest -> Exravasation between endothelial cells May go from capture straight to arrest

Question 50

What cell surface receptors mediate rolling?

Answer 50

- E-selectin and P-selectin receptors on endothelium | - CD44, CEA and PODXL on tumour cell

Question 51

What cell surface receptors mediate arrest?

Answer 51

- ICAM1 and VCAM1 receptors on endothelium | - Integrins on tumour cell

Question 52

How might a CTC begin to grow within a blood vessel?

Answer 52

Adherence of platelets onto CTC. Another CTC with platelets binds to a nucleated cell by platelet mediated capture and then subsequent growth occurs