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Flashcards in Metastasis Deck (40):

What is metastasis?

Spread of tumour to- and growth at- ectopic sites, via blood, lymphatics, intra-epithelial route, or transcoelomic


What is metastases?

The metastatic tumour lesion


What is invasion?

growth by infiltration and destruction of surrounding tissues
i.e. growth at the primary site


What are signs of invasion?

An uneven, ragged edge to the tumour.


What is a carcinoma?

malignant tumour derived from the epithelial cells


What is a sarcoma?

malignant tumour derived from mesenchymal cells


What is melanoma?

malignant tumour derived from neural crest cells


What is leukaemia

malignant tumour derived from circulating white blood cells


What is lymphoma

malignant tumour derived from the lymphatic system


What does a carcinoma have to overcome in order to metastasise?

The basement membranes, which act as a barrier


Describe the metastatic cascade

- local invasion
- neovascularisation/angiogenesis
- detatchment
- intravasation
- transport
- lodgement/arrest
- extravasation
- growth at ectopic site


What is the metastatic cascade?

process that cells need to go through in order to metastasise


What diameter does a tumour need to exceed to develop its own blood supply?

>1mm to facilitate the diffusion of nutrients and waste products


What is intravasation?

The process of getting into the circulation


What is extravasation?

The process of getting out of the circulation


What is occult metastases?

the growing metastatic cells at an ectopic region


What are the seven properties cells need in order to metastasise?

1 - reduced cell-cell adhesion
2 - altered cell-substratum adhesion
3 - increased motility
4 - increased proteolytic ability
5 - angiogenic ability
6 - ability to intravasate and extravasate
7 - ability to proliferate (locally and ectopically)


Which of the seven properties of metastatic tumour cells are common to invasion?

1 - reduced cell-cell adhesion
2 - altered cell-substratum adhesion
3 - increased motility
4 - increased proteolytic ability


Describe how reduced cell-cell adhesion can occur

Disrupted e-cadherin function

can be due to:
- lack of expression
- e-cadherin is present but has mutated to lose calcium binding site
- the e-cadherin promoter has been switched off
- beta cadherin, or APC mutated (molecules that interact with E-cadhein
- mutations in transcription factors that regulate e-cadherin (snail, slug, twist)


What is homotypic adhesion?

where the ligand and the receptor are the same molecule


Describe adherens junctions

- homotypic adhesion
- E-cadherins participate
- e-cadherin joined to linker proteins on inside of cell
- beta-catenin is bound to the e-cadherin
- alpha-catenin is bound to beta-catenin and actin-myposin skeleton


What is the correlation between malignancy and e-cadherin expression?

The less malignant a tumour cell is histologically, the more likely it is to express e-cadherin
(most of the time, but not always)


What are integrins?

Cell adhesion molecules that are integral to the plasma membrane and bind to extracellular matrix molecules

- found in basal epithelial cells and in focal adhesions of migrating cells


What is the role of integrins in metastasis?

If an endothelial tissue wants to become an endothelial tumour, it needs to switch the integrin containing junctions that fix you in place, and replace them with integrin containing junctions that facilitate movement

integrins bind to a different celladhesion molecule in a different cell type (known as heterotypic adhesion)

Specific integrin-ligand combinations have
been associated with malignant tumours. E.g.
vitronectin receptor - found in melanoma


What are the mechanisms in which integrins are involved in metastasis?

- may switch off so that the tumour cell can
escape in the first place
- change in integrin type so that focal
adhesions can be formed instead of hemidesmosomes
- adhesion to BM or blood vessel
- act as receptors for enzymes so that the tumour cells can degrade the stroma


What is HGF?

hepatocyte growth factor

HGF is a mitogen (growth factor), a motogen
(motility factor) and a morphogen with a
developmental role, e.g., in migration of limb
buds (potent in tube-like structures)


What is HGFs role in metastasis?

In cell cultures - can perturb e-cadherin between epithelial cells

If there is HGF expressed in the stroma and the tumour cells happen to express a c-met, then c-met will bind and stimulate the following events:
=> activation of c-met leads to =>tyrosine phosphorylation of b-catenin in tumour epithelial cells
=> disrupted ECD-mediated adhesion


Where is HGF roduced?

but produced by the stromal
cells in a tumour (cells in the tumour
microenvironment, TME).



Why is the tumour microenvironment important?

can determine the behaviour of the tumour through interactions between the tumour cells and the cells in the stroma


Name the two main families of proteases

- serine proteases
- matrix metaloproteinases


Give examples of serine proteases

urokinase plasminogen activator (uPA), plasmin bind to receptors on tumour cell surface (uPAR)
- heard about these in context of clotting. Can facilitate migration through the stroma


Give examples of MMPs

collagenases, gelatinases, stromelysins, membrane-type (MT)-MMPs
- soluble forms with ECM homology can bind to integrins (e.g., MMP-2 binds to avb3)
- produced by WBCs, associated with tissue / wound repair


What is the disadvantage of therapeutic agents targeting MMPs

- create significant side effects


Describe the role of VEGF

A cell in a hypoxic environment induces the expression of hypoxia inducible factor (a
transcription factor).

=> upregulation of expression of VEGF, which binds to receptors in the epithelial cells.

=> induce the endothelial cells to multiply to form tubes and to grow towards the tumour.

how you get new blood vessels growing towards the tumour.


Describe the properties of vessels supplying a tumour

new blood vessels are quite leaky, allowing fibrinogen and other proteins to leak out. If
there are procoagulants in the tumour environment, these will act on fibrinogen, converting it
into fibrin. This fibrin clot is a particularly good surface for epithelial cells to migrate on.


Describe how metastatic tumour cells are able to intravasate and extravasate

Behave like WBCs

Rolling and sticking is how white blood cells slow down, apply weak adhesions and then they
adhere more firmly to the vessel walls. This is a precursor for them moving into the surrounding
One of the molecules important for this is selectin, which is expressed on white cell surface


How are metastatic tumour cells able to proliferate?

tissue trophism for different tumours. I.e. preferential growth in different sites

mix of:

- The tumour cell is the seed, but it has to fall on
fertile soil, an appropriate tumour
microenvironment in order to grow.

- flow of blood supply


What is immunoediting?

the immune system shapes
what the tumour is like, depending on the
different types of immune cells that get into the
tumour microenvironment,


What are the different stages of immunoediting?

- tumour cells are killed off
- they sit in equilibrium with the surrounding
- one of the tumour cells escapes and is able to
grow despite the immune cells that are present


Give an example of a treatment developed to stop the tumour cells from escaping?

lymphocytes with the surface antigen CTL-associated antigen-4 generally
don’t attack tumour cells. If you could somehow disable that surface antigen, then you might be
able to reawaken their ability to re-attack tumour cells

Ipilimumab is targeting that particular molecule