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METASTASIS II:
Step 3: Local invasion
• Cell migration
b
...
Migration is not specific to cancer cells – particularly during:
a
...
b
...
e
...
2
...
Modes of migration:
1
...
For example, sperm cell
migration
...
Crawling – majority of cells in tissues use this mode
...
Fibroblasts, macrophages and neuronal growth cones use this mode
of migration
...
It is characterised by weak or
absent adhesion to the substratum with little or no ECM proteolysis
...
The actin cytoskeleton is a dynamic, filament-based protein network, that can
assemble and disassemble very rapidly
...
Actin exists at monomers that polymerise into filaments – that can be assembled
and disassembled very rapidly
...
These filaments can take different roles in the cell:
- Contractile bundles – anti-parallel to each other
- Gel-like meshwork – seen at the front of a migrating cell
- Fillopodia/Microspikes – tight, parallel bundles
...
It can be transitioned between these different states very quickly!
Locomotion Step 1- Protrusion:
1
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2
...
3
...
4
...
5
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Step 2 – Adhesion:
1
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Step 3 – Forward Movement:
1
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Sacromere-like contractions
b
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This force is different in the mesenchymal and amoeboid motility
...
In the mesenchymal cell, there is a little of contractility at the top of the cell,
compared to the rear of the cell where there is a lot more contractility that favours
the direction of movement
...
Whereas, in the amoeboid cells, the contraction is uniform around the entire cortex
and this is how the bleb is generated
...
The myosin acting with actin produces that contraction that then forces that bleb
out on the cell, and therefore these cells do not require as much tail retraction as the
mesenchymal cells
...
Active contractility is based on myosin contractility, and as that contractility occurs,
in fast moving cells they ‘rip themselves’ off the substrate and leave residues on the
matrix – passive
...
Slower moving cells have a more active process where the integrin mediated
adhesions are actively disassembled and is part of the migratory process – the
adhesions are disassembled and assembled as the cell moves
...
The net result is forward movement
...
One tumour does not adopt one
mode of migration – different examples of migration within that tumour
...
Cancer Cell Plasticity:
1
...
2
...
3
...
4
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5
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6
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7
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Control of Cell Plasticity:
1
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2
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e
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3
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4
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5
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6
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7
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8
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9
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Step 4: Intravasation
1
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2
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3
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4
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5
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6
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7
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8
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Step 5 – Survival in the Circulation:
1
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2
...
3
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- Monocytes and platelets may provide angiogenic cytokines
...
4
...
5
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6
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7
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Step 6 – Arrest in the vessel:
1
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2
...
3
...
4
...
5
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6
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7
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Step 7 – Extravasation:
1
...
2
...
3
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Step 8 – Growth at Secondary Sites:
1
...
2
...
3
...
e
...
4
...
5
...
e
...
6
...
7
...
8
...
9
...
Thus the breast cancer cell is
likely to find the soil in the lung better
...
The soil needs to be able to provide growth support, which will depend on adequate
local supply of growth factors and also depends on angiogenesis
...
It is important to note that not all disseminating cells will be angiogenic and
therefore the secondary deposit will remain dormant until the tumour cells acquire
the capacity for angiogenesis
...
Metastasis to the bone is common because there is a balance between the resident
cells: osteoclasts and osteoblasts
...
When the cancer cells enter the microenvironment, there are other stromal factors
that are secreting factors that are promoting the survival of the breast cancer cells,
such as CXCL12
...
As the tumour develops, it can produce factors that activate the osteoclasts, such as
RANKL, and the activated osteoclasts start to degrade the bone at a higher rate
...
Trapped in the bone are growth factors such as TGF-beta, which feeds back into the
macro-metastasis and promotes growth of the tumour cells at the secondary sites
...
People with metastasis to the bone often suffer from bone breaks due to the weak
bones caused by high osteoclast activity
...
This cross-talk between the osteoclasts and cancer cells is called a vicious cycle
...
The difference in latencies is due to the tumour cells lying dormant until they are
reactivated by the new resident stroma
...
For example, there could be inflammation in the tissue that activates these cells to
proliferate
...
Furthermore, there is also a co-evolution between the cancer cells and the tumour
microenvironment, which ultimately leads to the metastatic event
...
There is also a lot of heterogeneity in metastatic potential, in that, not all tumour
cells are equally capable of metastasis, possibly due to the stem cells properties
within the cells
...
This suggests that some cells have higher metastatic potential compared to other
cells and thus it should be possible to identify the genes involved
...
It has been identified that there are several genes that get switched off in the
metastatic clones to enable metastasis