Metastasis

Question 1

What is the sequence of events which occurs in metastasis?

Answer 1

detachment of tumour cells form their neighbours
invasion of surrounding connective tissue
intravasation into lumen of vessels
evasion of host defence mechanisms
adherence to endothelium at remote location
extravasation of cells from vessel lumen into surrounding tissue
survival and growth in new environment

Question 2

E-cadherin is expressed in many carcinomas. T/F?

Answer 2

True

Question 3

What proteinases are often over expressed in cancer cells?

Answer 3

Matrix metalloproteinases

Question 4

E-cadherin is calcium dependent and sometimes in cancer cells there is a mutation so that the calcium binding domain of E-Cadherin is missing. What effect does this have?

Answer 4

Unfunctional E-cadherin allowing aggressive tumour invasion

Question 5

What are integrins?

Answer 5

Cell-surface molecules that bind to extracellular matrix molecules

Question 6

Specific integrins seem to promote invasion and metastasis. Describe possible mechanisms by which this occurs

Answer 6

Decreased adhesion to the basement membrane surrounding the epithelium
increased migration through stroma
increased adhesion to basement membrane or endothelial cells of blood vessels

Question 7

Describe the mechanism by which HGF can induce epithelial cells to dissociate and scatter in culture.

Answer 7

HGF binds to c-met (a receptor tyrosine kinase) causing increased tyrosine phosphorylation of B-catenin which disrupts E-cadherin mediated adhesion

Question 8

What type of collagen do matrix metalloproteinases degrade and why is this relevant to metastasis?

Answer 8

Type four collagen - which makes up the basement membrane thus allowing tumour to break through the bm

Question 9

Describe the role of VEGF in metastasis

Answer 9

VEGF is expressed by hypoxic cancer cells
VEGF binds to its receptors on nearby endothelial cells causes these cells to migrate towards the tumour and start to form new blood vessels
the newly formed vessels are weak and leaky which allows fibrinogen to leak out and a clot to form
the clot provides a good surface for the endothelium to grow onto

Question 10

Tumour cells can exploit the abilities of lymphocytes to intravasate and extravasate. T/F?

Answer 10

True

Question 11

What are the ten major characteristics of cancer cells?

Answer 11

Unlimited multiplication
Escape from growth suppressors
Promotion of invasion and metastasis
Resistance of apoptosis
Stimulation of angiogenesis
Maintenance of proliferative signalling
Elimination of cell energy limitations
Evasion of immune destruction
Genome instability and mutation
Tumour enhanced inflammation

Question 12

Metastasis is the leading cause of cancer related death. How does metastasis cause death?

Answer 12

Physical obstructions
Compromised organ function
Competing with healthy tissue for nutrients and oxygen

Question 13

How do mesenchymal cells differ from epithelial cells?

Answer 13

Loose or no interactions between cells
No cell-cell junctions
No clear apical/basolateral membranes
No apicobasal polarised distribution of organelles and cytoskeleton
Mobile and sometimes invasive

Question 14

E-cadherin binding is homotypic. What does this mean?

Answer 14

E-cadherin on one cell binds to e-cadherin on another cell

Question 15

What molecules facilitate the binding of E-cadherin to the actin cytoskeleton?

Answer 15

alpha and beta catenin

Question 16

E-cadherin expression can be disrupted in cancer by silencing of the CDH1 promoter. How does this occur?

Answer 16

Methylation mutations in proteins which interact with e-cadherin such as beta catenin

Question 17

What transcription factors normally suppress E-cadherin and can be over-expressed in cancer cells?

Answer 17

Slug
Snail
Twist

Question 18

Integrins exhibit bidirectional signalling. T/F?

Answer 18

True

Question 19

How many possible heterodimers can be formed from integrins?

Answer 19

24

Question 20

Where are integrins found?

Answer 20

basal epithelial cells

focal adhesions of migrating cells

Question 21

In what ways is altered intern expression useful for cancer cells?

Answer 21

Supports oncogenic growth factor receptor signalling
Allows cell migration and invasion
Allows extravasation from blood vessels
Causes colonisation of metastatic sites
Allows survival of circulating tumour cells

Question 22

In metastasis, why cells secrete HGF?

Answer 22

Stromal cells

Question 23

What protein is activated by urokinase plasminogen activator?

Answer 23

Plasminogen is activated to plasmin

Question 24

What is the function of cathepsin K collagenolytic activity?

Answer 24

Matrix degradation

Question 25

What type of cancers commonly spread through the lymphatic system?

Answer 25

Carcinomas e.g. breast, colon and lung

Question 26

What type of cancers commonly spread through the blood?

Answer 26

Sarcomas | Some carcinomas such as kidney, colorectal and prostate

Question 27

What type of cancers commonly spread through transcoelomic spread?

Answer 27

Cancers which originate in the peritoneal cavity such as ovarian and colorectal

Question 28

What steps are involved in intravasation?

Answer 28

Attachment degradation of basement membrane diapedesis new leaky blood vessel formation

Question 29

What steps are involved in extravasation?

Answer 29

Attachment degradation of basement membrane diapedesis new structural sound blood vessel formation

Question 30

Most cancer cells do not survive transport in the blood. Why is this?

Answer 30

shear stress of blood flow immune detection anoikis

Question 31

What is anoikis?

Answer 31

Form of programmed cell death which occurs in anchorage-dependent cells when they detach from the ECM

Question 32

Cancer cells in the blood start to slow down and marginalise then roll along the endothelium. What molecules mediate this?

Answer 32

Selectins

Question 33

The arrest of cancer cells on the endothelium during extravasation is mediated by which molecules?

Answer 33

Integrins

Question 34

Which molecules mediated diapedesis in extravasation of cancer cells?

Answer 34

Junctional adhesion molecules

Question 35

Spread and crawling of cancer cells. along the endothelium in extravasation is mediated by which molecule?

Answer 35

Cell adhesion molecules

Question 36

What are selectins?

Answer 36

Carbohydrate binding transmembrane molecules

Question 37

What is the main physiological function of selectins?

Answer 37

mediate leukocyte recruitment to sites of inflammation or to lymphoid tissues

Question 38

Enhances expression of selection ligands by cancer cells is correlated with metastasis and a poorer prognosis. T/F?

Answer 38

True

Question 39

Define angiogenesis

Answer 39

The formation of new vessels from existing vasculature

Question 40

When cancer cells become hypoxic, which transcription factor mediates VEGF production?

Answer 40

Hypoxia inducible factor (HIF)

Question 41

What molecules usually inhibit angiogenesis?

Answer 41

Thrombospondin Endostatin Tumstatin Angiostatin

Question 42

Angiostatin is a fragment of....?

Answer 42

Plasminogen

Question 43

Endostatin is a fragment of....?

Answer 43

Collagen type XVIII

Question 44

Tumstatin is a fragment of....?

Answer 44

Collagen type IV

Question 45

What are the two models which determine where metastasis occur?

Answer 45

Seed and soil hypothesis | Mechanical model

Question 46

Describe the mechanical theory of metastasis?

Answer 46

Blood flow patterns determine which organ the cancer cells travel to first and the relative size of cancer cells and capillaries leads to the efficient arrest of most circulating cancer cells in the first capillary bed that they encounter

Question 47

The tumour microenvironment contains cancer associated fibroblasts. What do these secrete?

Answer 47

MMPs Cytokines IL-8 VEGF

Question 48

The tumour microenvironment contains cancer associated pericytes. What is the role of pericytes in cancer?

Answer 48

Low pericyte coverage results in leaky vessel structure which facilitates tumour cell invasion and extravasation

Question 49

How do M1 and M2 macrophages differ in their response to tumour?

Answer 49

M1 macrophages are tumorocidal | M2 macrophages promote tumour growth

Question 50

A large abundance of tumour associated macrophages is associated with poor clinical outcomes. T/F?

Answer 50

True

Question 51

The tumour microenvironment contains tumour associated macrophages. What do these secrete?

Answer 51

MMPS and growth factors

Question 52

Sustaining proliferative signalling is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 52

EGFR inhibitors

Question 53

Evading growth suppressors is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 53

Cyclin dependent kinase inhibitors

Question 54

Avoiding immune detection is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 54

Immune activating anti-CTLA4 monoclonal antibodies

Question 55

Enabling replicative immortality is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 55

Telomerase inhibitors

Question 56

Tumour promoting inflammation is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 56

Selective anti-inflammatory drugs

Question 57

Activating invasion and metastasis is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 57

inhibitors of HGF / c-met

Question 58

Inducing angiogenesis is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 58

inhibitors of VEGF signalling

Question 59

Genome instability and mutation is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 59

PARP inhibitors

Question 60

Resisting cell death is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 60

Proapoptopic BH3 mimetics

Question 61

Dysregulating cell energetics is a hallmark of cancer. What type of drugs can be used to combat this?

Answer 61

Aerobic glycosides inhibitors