CELLULAR

MECHANIS
M OF
INVASION
AND
METASTASI
S
Asraf Amirullah
KEY LEARNING OUTCOME
Definition
Factors Influencing Tumour Invasion
Invasion - Metastasis Cascade
DEFINITION
Invasion - direct extension and penetration by tumour cells into
neighbouring tissues
Metastasis - process whereby malignant tumours spread from their
site of origin (primary) to form other tumours (secondary) at distant
site.
The spread of cells throughout the body results in physical
obstruction, competition with normal cells for nutrients and
oxygen, and invasion which interfere with organ function.
FACTORS INFLUENCING TUMOUR INVASION
Abnormal or increased motility:- malignant cells are more mobile
than their normal counterparts
Secretion of proteolytic enzymes:- matrix metalloproteinases
(MMP) are secreted by malignant cells- digest surrounding
connective tissue (eg: interstitial collagenases degrade collagen Type
I, II and III)
Decreased cellular adhesion- Loss of surface adhesion molecules,
eg: cadherins enable migration of individual cells
THE INVASION-METASTASIS CASCADE
1. Localised invasion
2. Intravasation
3. Transport
4. Extravasation
5. Formation of micrometastasis
6. Colonisation
1. LOCALIZED INVASION

In order for cells of primary

tumour to invade into their local
environment, cells must break free
from the normal molecular
constraints that link adjacent cells
to each other (cell adhesion
molecules, E-cadherin, catenin).
The best characterised alteration
involves loss of E-cadherin by the
carcinoma cells
E-Cadherin
Transmembrane glycoprotein. Mediate homotypic adhesion between
cells.
It is an important epithelial cell-to-cell adhesion molecule, forming,
forming adherens junctions between adjacent epithelial cells
Increased expression of E-cadherin is associated with prevention of
invasion and metastasis, whereas decreased expression is known to
potentiate it
E-cadherin is encoded by the gene CDH1
Matrix Metalloproteinases (MMPs)
Invasion of tumour cells into surrounding tissue requires the action
of specific protease that degrade a path through the ECM and
stroma.
The most important effectors are matrix metalloproteinases (MMPs)
In some tumours, invading carcinoma cells make their own
proteases, while in others, bulk of these proteases are secreted by
macrophages, mast cells and fibroblasts in the tumour stroma.
The epithelial-mesenchymal transition (EMT)
It is a prominent means by which neoplastic epithelial cells can
acquire the ability to invade, resist apoptosis and disseminate
It involves the conversion of a sheet of closely connected
epithelial cells into highly mobile mesenchymal cells
Common in early embryogenesis and in wound healing,
reactivated in cancer cells.
OTHER MODES OF INVASION
Amoeboid invasion:- Cancer cells show morphologic plasticity
enabling them to slither through existing interstices in ECM rather
than clearing a path for themselves
Collective invasion:- Group of cancer cells advancing in masses into
adjacent tissueseg: Squamous cell carcinoma
2. INTRAVASATION
It is the entry of the tumour cell
into a blood or lymphatic vessel
It requires several steps- Tumour
cells must attach to the stratal
face of the vessel- Degrade the
basement membrane using
MMPs- Pass between the
endothelial cells (transendothelial
migration) into the bloodstream
Influenced by the structural
properties of the vessel: New
blood vessels stimulated by
tumour, leaky and tortuous
allowing easy access.
3. TRANSPORT
Once the cancer cells intravasated
into the lumen of a blood or
lymphatic vessels, they may travel
with blood or lymph to other areas of
the body
However, cancer cells require
anchorage to solid substrates to
survive. Without such attachment, the
migrating cells may die of anoikis.
(Apoptosis induced by inadequate
cell matrix interactions)
Hydrodynamic shear forces in
circulation may tear the wandering
cancer cells apart. To enhances
survival, it attract a group of
platelets, called emboli, to escort
them through circulation.
4. EXTRAVASATION
It is the escape of tumour cell from
blood vessel or lymphatic, to
penetrate the surrounding tissues.
The steps are in reverse to the
intravasation:- Attachment to
endothelial side of blood vessel (E
- selection)- Pass through the
endothelial cells and basement
membrane- Migrate to the
surrounding stroma
5. FORMATION OF MICRO METASTASIS
Once the metastasise cancer cells arrive within tissue parenchyma,
the form small clumps or minute colonies of disseminated cancer
cells called micro metastasis
These micro metastases may lack certain hallmark capabilities
necessary for vigorous growth, such as ability to activate
angiogenesis
Moreover, nutrient starvation can induce intense autophagy that
causes cancer cells to shrink and adopt a state of reversible
dormancy.
5. FORMATION OF MICRO METASTASIS
Such cells can resume active
growth and proliferation when
permitted by changes in tissue
microenvironment such as
increased availability of nutrients
or inflammation due to infection or
wound healing.
Other mechanisms of
micrometastatic dormancy involve
antigrowth signals of normal tissue
ECM and tumour suppressing
actions of immune system.
6. COLONISATION
The final step of the micrometastasis growth into macroscopic
tumours.
Most difficult step as the foreign tissue environment might not
provide the newly arrived cancer cells the growth and survival
factors, the primary tumour provided them.
Without physiological support, metastasising cells may die rapidly,
or survived for extended periods as micrometastasis that can only be
detected microscopically, and rarely beyond this size.
Probability of an individual cancer cell to successfully completing
all steps of invasion-metastasis cascade is very low. Low rate of
success is called metastatic insufficiency.
CONCLUSION
Invasion-metastatic cascade involved 6 steps.
Earlier steps of this cascade executed efficiently while the last step
involving colonisation succeeds only rarely due to limiting steps of
process.
By identifying these metastasis suppressor genes, drugs can be
developed to reactivate metastasis suppressor genes, promote
dormancy of micrometastatic colonies and prevent over metastasis.
SOURCE
Robbins Essential Pathology - Chapter 5: Neoplasia
Basic Sciences for the MRCS, 4th Edition - Chapter 8 Neoplasia
THANK YOU