Metastatic Cascade Flashcards

1
Q

What cancer cell properties offer an advantage for tumour growth and will be favoured as the disease progresses?

A

Phenotypic drivers
Cancer stem cell properties
Ability to invade
Ability to metastasise

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2
Q

What leads to the development of primary tumour?

A

A loss of growth control

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3
Q

What leads to the process of tumour dissemination?

A

A loss of positional control

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4
Q

What are the mechanistic steps in invasion (i.e the metastatic cascade)?

A

Breakdown of the epithelial basement membrane and invasion of the underlying stroma
Breakdown of a vessel wall and intravasation
Dissemination with blood vessles
Arrest on a vessel wall (adhesion or proliferation) and extravasation
Formation of micro-metastases
Formation of macro-metastases through colonization

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5
Q

What does epithelial integrity require?

A

Cells to adhere tightly to each other and the basement membrane
If the tumour is to become invasive then this must be lost through either a loss of adhesion or degradation

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6
Q

How does the loss of epithelial adhesion proteins occur?

A

There is a loss of E-cadherin and cytokeratin

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7
Q

How can a gain of new adhesion proteins and acquisition of the ability to move occur?

A

There is a gain of contractile fibres: vimentin, alph-smooth muscle actin to enable movement and fibronectin
Acquisition of adhesion molecules (N-cadherin and integrins) to facilitate interactions with the stroma

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8
Q

What are the steps involved in the process of invasion in a cancer cell?

A

Detachment from the primary tumour (via the down regulation of E-Cadherin expression)
Attachement to matrix components through gain of N-cadherin expression
Degradation of the extracellular matrix through secretion of proteolytic enzymes such as MMPs
Migration

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9
Q

What are the features of normal epithelium?

A
Well-organized
Apico-basal polarity
Adherens junctions with regular E-cadherins
Regular actin bundles
Cytokeratin
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10
Q

What are the consequences of an epithelial to mesenchymal transition?

A

This leads to a change in cell shape and motility

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11
Q

What are the molecular features of an epithelial to mesenchymal transition?

A

There is a loss of Cytokeratin expression, epithelial adherens junction protein (E-cadherin) and epithelial polarity
There is also a gain of fibroblast like shape, motility, invasiveness, mesenchymal gene expression, mesenchymal adherens junction protein (N-Cadherin), protease secretion, vimentin (intermediate filament) expression, Fibronectin secretion, PDGF receptor expression, alphavbeta6 integrin expression

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12
Q

What are the transcription factors which reactivate the mesenchymal gene expression programme?

A
Slug
Snail
Twist
Beta-catenin
E2A
Forkhead
Goosecoid
SIP1
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13
Q

What are the genetic and epigenetic changes and stromal factors which assist EMT?

A
TGFalpha
TGFbeta
TNFalpha
EGF
FGF
HGF
microRNAs
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14
Q

What are motogens?

A

These are proteins like growth factors which are sensed by cytoplasmic protrusions to cause positive chemotaxis
The movement induced by these factors requires energy from Rad-like GTPases that involve members of rhe Rho family ofG proteins
Rho proper
Rac and Cdc42

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15
Q

How does cell motility occur?

A

This is a co-ordinated process which involves a series of changes in the cytoskeleton as well as process of making and breaking contact with the matrix
The initial process of movement involves the formation of a leading edge
The cell then deploys integrins to create a new point of contact between the lamellipodium and the ECM
At the same time adhesion contact is broken at the trailing edge which liberates the cytoplasm and plasma membrane to redeployment to the leading edge as if the cell rolled forward

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16
Q

What are the functions of membrane bound MMPs in tumour cells?

A

These cause localized destruction of cell surface receptors like cadherins, integrin receptors, growth factor receptors and chemokines

17
Q

What are the functions of secreted MMPs from cancer cells?

A

These cause more generalized breakdown of extracellular matrix components like collagen, fibronectin, laminin and proteoglycans
Helps to mobilize and activate growth factors that are bound to ECM and in precursor form

18
Q

What is the event which contributes the most to a cancer cells ability to spread?

A

Epithelial to mesenchymal transition
The cellular characterisitcs acquired through EMT are likely similar in different types of cancer, however this is not an all or nothing process which could potentially explain why cells vary in their ability to move

19
Q

What stromal elements assist in invasion and metastasis?

A

Platelets to help dissemination of the cells through the blood

20
Q

How do platelets enhance metastatic spread of cancers?

A

They provide growth factors which support cell survival, protease enzymes which assist in invasion and adhesion molecules
These adhesion molecules assist in adherence between tumour cells and protect against turbulence of flowing blood
Shield cancer antigens and protect against NK cell killing
Trap cancer cell embolus
Provide a bridge between tumour cells and endothelium

21
Q

What occurs once tumour cells invade capillaries?

A

They will drain into venules and then into the large circulation, from most tissues this means the next capillary be the tumour will encounter will be the lung though the gut, spleen and pancreas all drain via the hepatic portal vein and therefore encounter the liver capillary bed first
For this reason the liver and lung are the most common sites of metastases

22
Q

How does extravasation lead to the formation of micro-metastasis?

A

In the tissue where cancer cells extravaste they often find a new type of stromal environment which lacks the signals which previously allowed them to undergo an EMT which can often result in a reversal of the process known as MET once these cells have established their ability to survive in the new stroma a micrometastasis has been formed

23
Q

What is colonization?

A

This is the most inefficient and least effective process in the metastatic cascade and is strongly influenced by tissue properties as it referes to the generation of a macrometastases from micrometastases

24
Q

What are the functional steps in cancer progression?

A

EMT which ends with dormant micrometastases
Survival and colonization at distant sites which will end with micrometastases that are able to grow into macrometasastes
Macrometastases and secondary dissemination which creates a shower of metastatic cells and a widely disseminated disease

25
Q

How does the tissue site contribute to the development of metastases?

A

Certain tumour cells will favour interactions with host cells in selected sites
These interactions involve cells, matrix components as well as growth factors and cytokines and are organ specific

26
Q

What are examples of metastatic tropism?

A

This is when there is a particular organ preference for metastases and includes prostate and breast cancers which often metastases in bone which cannot be explained through the haemodynamic process and must be a result of the seed-and-soil factors

27
Q

What are the factors which influence bony metastases?

A

IL-11 and PTHrP
Osteoclast activity predominates in breast cancer and osteoblasts in prostate cancer (though bone turnover is a continuum)

28
Q

What are the interactions between oesteoclasts and oesteoblasts which regulate bone turnover?

A

Oesteoblasts produce RANKL which activates osteoclast precursors to become oesteoclasts which degrades mineralized bone
Oesteoblasts also produce OPG which inhibits the actions of RANKL

29
Q

What occurs in oesteolytic metastases like breast cancer/

A

The calcium apatite crystals have been dissolved away by the acid, a meshwork of collagen rich ECM is exposed where mitogens and growth factors are stored which will now become available to cancer cells
An army of oesteoclasts east up the bine which can compromise bone structure leading to fractures

30
Q

What are the factors which contribute to pre-metastatic tissue niches?

A

This is when host cells play a key role in influencing metastatic behaviour
Bone marrow derived haematopoietic progenitors expressing VEGF-R1 proceed arrival of metastatic cells in tissues
Other contributing factors include upregulation of specifc integrins, ECM ligands, inflammatory chemoattractants, metalloproteases, bioavailability of TGFbeta, TNFalpha and hypoxia induced factors
Microvesicles derived from cancer cells or platelets can transfer bioactive molecules which stimulate cell growth, invasion metastasis and angiogenesis

31
Q

What are the points of therapeutic intervention against bone metastases?

A

Biphosphates like pamidronate and zoledronic acid, these bind to calcium apatite which is ingested by oesteoclasts and is toxic to them
Denosumab which is a monoclonal antibody against RANKL

32
Q

What are the treatment options for metastatic cancer?

A

Solitary metastases can be treated with radiotherapy and surgery
Limited success in the development of drugs that would target metastases specifically such an integrin inhibitors, metalloprotease inhibitors, anti-coagulatents, anti-platelet agents and anti-angiogenic agents