Invasive Cancer

Question 1

How are organs defined?

Answer 1

By basement membranes.

Question 2

What are basement membranes made up of?

Answer 2

Extracellular matrix proteins- laminins, collagen and proteoglycans

Question 3

What is the extracellular matrix?

Answer 3

Complete meshwork of proteins and carbohydrates

Question 4

What does collagen/ proteoglycans provide the ECM with?

Answer 4

Structural integrity to tissues.

Question 5

How is the ECM connected to other cells?

Answer 5

Directly connected to cells it surrounds- acts as an interface between cells and other structures like blood vessels.

Question 6

How can cancer cells move into the bloodstream and then around the body>T

Answer 6

By penetration of the ECM

Question 7

What are cadherins?

Answer 7

Type of cell adhesion molecule which bind to each other and the ECM

Question 8

What is E-cadherin involved in?

Answer 8

Cell-cell adhesion of epithelial cells.

Question 9

What do epithelial cancers often show?

Answer 9

Downregulation and mutation of E-cadherin.

Question 10

What is the mechanisms of metasisis?

Answer 10

Tumour cells spread from the primary tumour.
This is subclonal meaning that the cells are genetically identical but differ by mutations.

Question 11

Name the two different mechanisms used by metastasis.

Answer 11

Monoclonal
Polyclonal

Question 12

Name the two different patterns used by metastasis.

Answer 12

Linear
Branched

->this gives different mutations

Question 13

In order for cancer cell to spread, what must they beomce?

Answer 13

Must become mobile

Question 14

What is epithelial mesenchymal transition (EMT)?

Answer 14

Conversion of closely connect epithelium cells to independent mesenchymal cells with the ability to move and invade their local environemnt.

Question 15

Is the process of EMT reversible?

Answer 15

Yes

Question 16

Where does EMT occur?

Answer 16

-Usually in embryogenesis but also occurs in cancer metastasis.

Question 17

What are the five major steps that cells undergo in order to reach metastasis>

Answer 17

1. Invasion
2. Intravasation
3. Transport
4. Extravasation
5. Colonisation

Question 18

Do all cells found it the primary tumour have the ability to metasisise?

Answer 18

No

Question 19

Describe the process of invasion.

Answer 19

EMT begins with signals from tumour stroma (HGF, TGF-beta) which stimulates kinase receptors (EFGR) & triggers MAPK pathway

Question 20

Name two cell adhesion molecules which help w invasion.

Answer 20

Cadherins ( calcium dependent transmembrane proteins) & Catenins (protein inducing gene expression)

Question 21

What do integrins do?

Answer 21

Enable cells to “break free” becoming mobile by modifying the membrane distribution.

Question 22

What do proteases do?

Answer 22

Make the pathway through ECM by the destruction of tissues.
Matrix Metalloproteins contribute to loss of cell junctions

Question 23

What can mutation within E-cadherin lead to?

Answer 23

Inadequate cell-cell adhesion and distortion of cell shape.

Question 24

Describe intravasation.

Answer 24

Entry into blood or lymphatics.
->Tumour cell attaches to stromal side of basement membrane
->MMPs and serin proteases help to degrade basement membrane
->Tumour cell passes between the endothelial cells and off into the
bloodstream (transendothelial migration)

Question 25

Describe transport.

Answer 25

Circulating tumour cells travelling in a way one system around the body. They can travel as a single cell or within a group of platelets (emboli). Certain cancer cells have favoured metastatic sites.

Question 26

What are tumours in the bloodstream referred to as?

Answer 26

Circulating tumour cells (CTC's).

Question 27

What is the first pass organ?

Answer 27

The first organ on route which lies downstream from the primary tumour. For example, lungs are the first organ down the pathway from the breast.

Question 28

Describe extravasation.

Answer 28

* Exit of tumour cells from bloods vessels into distant tissues * Tumour cells become trapped in capillaries * Reverse of intravasation

Question 29

What is E-selectin and what does it do?

Answer 29

->Calcium dependent receptor -> enables attachment of the cancer cell to the endothelium surface of blood vessels and passage through the endothelium (transendothelial migration).

Question 30

How is the point of metastasis determined?

Answer 30

By the point of extravasation but also the microenvironment.

Question 31

What must the environment be like to allow tumours to grow?

Answer 31

Environment must be favourable and create new blood vessels (angiogenesis) for nutrients and oxygen.

Question 32

What form do dormant cancer cells take up?

Answer 32

Micrometastases

Question 33

What is angiogenetic switch dependant on?

Answer 33

Inhibitors and inducors.

Question 34

List some anti - angiogenic factors

Answer 34

Angiostatin Endostatin Prolactin Protein 53 (p53) Thrombospondin 1 & 2

Question 35

Name some pro-angiogenic factors.

Answer 35

VEGF Fibroblast growth factor Hepatocyte growth factor Epidermal growth factor Platelet derived growth factor

Question 36

What are the majority of angiogenetic inducers?

Answer 36

Grwoth Fcators

Question 37

What are the majority of angiogenetic inducers?

Answer 37

Growth Factors

Question 38

Which angiogenetic inducer is the most important and induces angiogenesis?

Answer 38

VEGF

Question 39

Name the five members of the VEGF family

Answer 39

A B C D Placental growth factor

Question 40

Which member of the VEGF family is secreted by a large number of tumour cells?

Answer 40

VEGF-A

Question 41

How do the members of the VEGF family transmit their signals?

Answer 41

Via three VEGF receptors.

Question 42

How is VEGFR activated?

Answer 42

Must be phosphorylated.

Question 43

How can tumour cells promote angiogenesis?

Answer 43

They stimulate nearby cells to produce VEGF and in turn promote angiogenesis

Question 44

What is VEGFR1?

Answer 44

Inhibitory and regulates the mito VEGF-A available.

Question 45

What does VEGFR2 do?

Answer 45

Enables angiogenesis.

Question 46

What is VEGFR3 required for?

Answer 46

The formation of lymphatic vessels.

Question 47

What do angiogenic inhibitors do?

Answer 47

Help to regulate angiogenesis.

Question 48

What can plasminogen can be cleaved to release?

Answer 48

Angiostatin- angiogenic inhibitor

Question 49

What does endostatin do?

Answer 49

Blocks the MAPK pathway thus inhibiting gene expression.

Question 50

What is Concomitant resistance?

Answer 50

Enabling growth in distant metastases ->can be as a result of surgery which activates previously dormant cells.,

Question 51

What is the angiogenic switch controlled by?

Answer 51

Hypoxia

Question 52

How do tumours create a hypoxic environment?

Answer 52

By activating HIF1 alpha & beta subunit triggering VEGF.

Question 53

Name one drug which inhibits angiogenesis.

Answer 53

TKI Afatanib