Outline of disease processes

Question 1

Name the three kinds of cancer cells.

Answer 1

Epithelial cells
Mesoderm cells
Glandular cells

Question 2

Describe epithelial cancer cells.

Answer 2

They are squamous, cuboidal or columnar.
They are responsible for 85% of cancers.
= Carcinomas

Question 3

Describe mesoderm cancer cells.

Answer 3

These are one of three germ cell types.
Mesoderm cells are are sandwiched between endoderm and ectoderm layers.
They form blood vessels and connective tissue.
Responsible for bone or muscle cancers.
= Sarcomas

Question 4

Describe glandular cancer cells.

Answer 4

Exocrine or endocrine glandular epithelial cells.
Cancers of these cells are
= Adenocarcinomas.

Question 5

Define “gene silencing”

Answer 5

Interruption or suppression of gene expression at transcriptional or translational level.

Question 6

Describe an immune checkpoint.

Answer 6

This is a built in control mechanism that maintains self tolerance during an immune response.

Question 7

Define a somatic mutation.

Answer 7

Most common is acquired.

Question 8

Define a germline mutation.

Answer 8

Hereditary.

Question 9

Describe the composition of basement membrane.

Answer 9

The basement membrane is made of the extracellular matrix proteins: laminins, collagens and proteoglycans.

Question 10

Describe the role of the extracellular matrix in cancer spread.

Answer 10

The extracellular matrix is directly attached to the cells it surrounds.
By penetrating the matrix, cancer cells can move into the bloodstream and around the body.

Question 11

Describe the role of cadherins in cancer spread.

Answer 11

Cadherins are a type of cell-cell adhesion molecules.
(CAM).
They bind cells to each other and to the ECM.
E-cadherin is involved in cell-cell adhesion of epithelial cells.
Epithelial cancers often show downregulation and mutation of E-cadherin.

Question 12

Describe the mechanism of metastasis.

Answer 12

This is the spread of cancer cells, sub-clonally, from the primary tumour.
This means that the cells are genetically identical but differ by mutations.
Occurs in a monoclonal or polyclonal mechanism.
And can occur in a linear or branched pattern.

Question 13

Describe epithelial mesenchymal transition (EMT).

Answer 13

EMT is the conversion of closely connected epithelial cells becoming independent mesenchymal cells with the ability to move and invade their local environment.
This is a reversible process.
EMT usually occurs in embryogenesis - also occurs in cancer metastasis.

Question 14

Describe the steps involved in the journey to metastasis.

Answer 14

Invasion
Intravasation
Transport
Extravasation
Colonisation

Question 15

Describe the initiation of EMT in invasion stage of cancer.

Answer 15

Epithelial-Mesenchymal transition begins with signals from tumour stroma (HGF,TGF-Beta) stimulate kinase receptors (EFGR) and trigger the MAPK pathway.

Question 16

Describe the role of cell adhesion molecules in invasion.

Answer 16

CAM’s - cadherins (calcium dependant transmembrane proteins) and catenins (protein inducing gene expression)

Question 17

Describe the role of integrins in invasion.

Answer 17

Integrins allow cancer cells to break free from the ECM and give the cells mobility.

Question 18

Describe the role of proteases in invasion.

Answer 18

Proteases degrade a pathway through the ECM, (matrix metalloproteinases) cleave the extracellular remaining cadherin - contributing to the loss of cell junctions and also degrade structural components of the ECM.

Question 19

Define intravasation.

Answer 19

This is the entry of tumour cells into blood or lymphatic vessels

Question 20

Describe intravasation in the journey to metastasis.

Answer 20

The tumour cell attached to the stromal side of the basement membrane.
MMPs (Matrix metalloproteases) and serin proteases help to degrade the basement membrane so that the tumour cell can pass between the endothelial cells and off into the bloodstream
= trans endothelial migration

Question 21

Describe the transport of tumour cells in the journey to metastasis.

Answer 21

Tumour cells in the blood stream are called circulating tumour cells (CTCs).
These cells can be solo or clumped. They flow unidirectionally.
Certain cancers can favour different sites of metastasis.
This can be determined by the “first pass organ” (e.g. lung is the first pass organ of the breast).

Question 22

Describe extravasation.

Answer 22

This is the reverse of intravasation.
(At the endothelial side of the blood vessel) the basement membrane is degraded and the tumour cells migrate into the stoma.

Question 23

Describe the role of E-selectin in extravasation.

Answer 23

E-selectin is a calcium dependent receptor which enables attachment of the cancer cell to the endothelium surface of blood vessels and passage through the endothelium (trans endothelial migration)

Question 24

Describe colonisation in the journey to metastasis.

Answer 24

NOTE: The site of metastasis is determined by the point of extravasation but also the microenvironment.
The environment must be favourable - for the tumour to grow it must create new blood vessels (angiogenesis) for nutrients and oxygen.
Cells can spread but NOT colonise - dormant (micrometastases).

Question 25

Describe the role of angiogenesis in the spread of tumours.

Answer 25

Angiogenesis is the formation of new blood vessels. Occurs by sprouting.
Angiogenic switch is dependent on inhibitors and inducers (need to be balanced).

Question 26

Describe the role of angiogenic inducers (VEGF - “star player”)

Answer 26

VEGF (vascular endothelial growth factor).
VEGF family has 5 members : A-D and placental growth factor.
Tumour cells can also stimulate nearby cells to produce VEGF and in turn promote endothelial cell proliferation and ANGIOGENESIS.

Question 27

Describe the role of VEGF receptors 1-3.

Answer 27

1) Inhibitory and regulated amount of VEGF available.
2) Enables angiogenesis
3) Required for formation of lymphatic vessels

All must be phosphorylated to become activated.

Question 28

Describe the role of angiogenic inhibitors.

Answer 28

Help to regulate angiogenesis. (and the angiogenic switch)
Plasminogen is cleaved to form angiostatin.
Endostatin blocks the MAPK pathway thus inhibiting gene expression.

Question 29

Define “concomitant resistance”

Answer 29

This refers to enabling growth in distant metastases.

Question 30

Describe the involvement of hypoxia in the angiogenic switch.

Answer 30

Tumours create a hypoxic environment. (hypoxia controls angiogenic switch).