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Metastasis and

Invasion
Invasion refers to the direct extension and penetration by cancer
cells into neighbouring tissues. The proliferation of transformed
cells and the progressive increase in tumour size eventually leads
to a breach in the barriers between tissues, leading to tumour
extension into adjacent tissue. Local invasion is also the first
stage in the process that leads to the development of secondary
tumours or metastases.

Metastasis, from the Greek methistanai, meaning to move to


another place, describes the ability of cancer cells to penetrate
into lymphatic and blood vessels, circulate through these systems
and invade normal tissues elsewhere in the body.
Epithelial and mesenchymal cancer cells have to invade:
Basement membrane
Capsule (if present)
Penetrate surrounding stroma resulting in local invasion

After penetration, metastasis and distant spread takes place.


The tumor cells have to break through the primary mass, enter
blood vessels or lymphatics and produce secondary growth at
distant site.

The metastasis cascade is divided into:


Invasion of extracellular matrix
Vascular dissemination and homing of tumor cells
Invasion of Extracellular Matrix
Extracellular matrix consists of:
Basement membrane
Interstitial connective tissue

Steps:
Detachment of tumor cells from each other (problem in
adhesion molecules)
Degradation of extracellular matrix/basement membrane
Attachment to matrix components
Migration of tumor cells
1. Detachment of tumor cells from each other
a. Down regulation of E. cadherin expression

Normal cells are attached to each other with adhesion molecules:


-Cadherin family
-E-cadherin

Normal functioning of adhesion molecules is required for survival of epithelial cells, if


there is some problem, they detach from each other.

So tumor cells are detached from each other when adhesion molecules are not
expressed properly.
b. Mutations in genes for catenin

Catenin is a protein that lies under cell membrane.


It is linked with E cadherin, which then functions
properly.
Mutations in gene for catenin also reduce the function
of E cadherin.
2. Degradation of ECM/basement membrane

a. Release of proteolytic enzymes by tumor cells


Cathepsin D
Urokinase
Plasminogen activator
Matrix metalloproteinases (type IV collagenases)

Normally inactivated by anti-proteases. Balance between


proteases and anti-proteases is disturbed.
b. Role of collagenases (MMPs)
Several invasive carcinomas, sarcomas produce high
levels of these enzymes.
In situ carcinoma and adenoma produce less
collagenases.
Inhibition of collagenases activity reduces metastasis in
experimental animals.
c. Cells involved in secretion of proteolytic enzymes

By tumor cells themselves.


Tumor cells induce other cells to secrete these proteolytic
enzymes.
These are stromal fibroblasts and macrophages.

d. Migration by amoeboid movement An alternative


mechanism to pass through ECM

No need for proteolysis.


Squeeze through gaps.
3. Changes in attachment to matrix components

a. Normal epithelial cell receptors


Normal epithelial cells express integrin receptors for basement
membrane laminin and collagen, (integrin laminin bind each other)
Loss of adhesion will lead to apoptosis of cells.

b. Modification of receptors for survival of tumor cells


Loss of adhesion molecules but no apoptosis. Matrix
metalloproteinases generate more sites over collagen and laminin
which stimulate tumor cells propagation and migration through
matrix.
4. Migration of tumor cells

a. Movement of tumor cells through matrix


Cells detach from matrix, contract the actin cytoskeleton and re-attach at
leading edge.

b. Mediators involved in migration


Tumor cells derived cytokines -autocrine motility factor.
Break down products from matrix destruction, chemotactic factor for
tumor cells
Growth factors released from stromal cells (fibroblasts) hepatocyte
growth factor scatter factor.

Under their action, tumor cells make a path between loose ECM and
migrate.
ii. Vascular Dissemination and
Homing of Tumor Cells
Intravasation of tumor cells

Intravasation of tumor cells involves:


Adhesion molecules
Proteolysis (of basement membrane of blood vessels)

Tumor cells in circulation are


Vulnerable to destruction and apoptosis due to loss of adhesion (anoikis)
Anoikis is the phenomenon in which tumor cells can undergo death
when come into circulation.
Formation of tumor emboli within vessels

Tumor cells tend to aggregate with each other by:


Homotypic adhesion among tumor cells
Heterotypic adhesion between tumor cells and blood
cells, particularly platelets.

Extravasation of tumor emboli involves:


Adhesion to vascular endothelium
Adhesion molecules (i.e. Integrins, Laminin, CD44
receptors)
Migration through basement membrane is by proteolytic enzymes.

Reason for organ selectivity


1. Mechanistic theory
Determined by pattern of blood flow

2. Seed and soil theory


The provision of a fertile environment in which compatible tumor
cells could grow.
Formation of secondary deposits

1. Along the natural pathway


First capillary bed available

2. By organ tropism
Affinity of an organ for neoplastic cells
Endothelial cells of vascular beds of certain organs may express ligands for
tumor cells receptors
Some target organs may liberate chemoattractants that invite tumor cells at
that site.
Some target tissues may be unpermissive for tumor cells to grow there e.g.
skeletal muscles.

Due to release of mediators by skeletal muscles, secondary deposits are not


usually seen there.
Pathways of Spread

1. Direct spread to body cavities

Body cavities include the pleural, peritoneal, pericardial


cavities and the joint spaces.
Common examples are appendix, ovaries cancers.
Adenocarcinoma of ovary spreads to liver, lungs etc.
2. Lymphatic vessels
Breast carcinoma spreads via axillary, internal
mammary nodes.
Sentinel lymph nodes
1st lymph node in drainage. Dye is injected into breast,
lymph node taking dye first is the sentinel lymph node.
When a lymph node is involved, the whole group is
actually involved, even if not enlarged (micro-deposits
may be present).
3. Hematogenous spread

Typical of sarcomas but carcinomas also show vascular


invasion.

Venous spread
Due to thicker walls, some cancer tumor cells follow venous
drainage and deposit in 1st capillary bed they encounter.
Lungs and liver are the most common sites

Arterial spread
Less commonly involved due to thicker walls.