Molecular mechanism of invasion and metastasis of malignant tumours
Hallmarks of cancer
1) Self-sufficiency in growth signals
2) Insensitivity to growth-inhibitory signals
3) Altered cellular metabolism
4) Evasion of apoptosis
5) Limitless replicative potential (immortality)
6) Sustained angiogenesis
7) Invasion and metastasis (spread)
8) Evasion of immune surveillance
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Invasion and metastasis involve complex interactions involving cancer cells, stromal cells,
and the extracellular matrix (ECM).
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These interactions can be broken down into a series of steps consisting of local invasion,
intravasation into blood and lymph vessels, transit through the vasculature, extravasation from the
vessels, formation of micrometastases, and growth of micrometastases into macroscopic tumours.
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The metastatic cascade can be subdivided into two phases:
(1) Invasion of ECM (local invasion)
(2) Vascular dissemination and homing of tumour cells
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Invasion of ECM (=Local invasion)
Invasiveness is the feature that most reliably distinguishes cancers from benign tumours.
Cancers lack well-defined capsules and penetrate the margin and infiltrating adjacent
Structures.
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This infiltrative mode of growth makes it necessary to remove a wide margin of
Surrounding normal tissue when surgical excision of a malignant tumour is attempted. Surgical
pathologists carefully examine the margins of resected tumours to ensure that they are devoid of
cancer cells (clean margins).
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The process of local invasion and distant spread involves passage through barriers before
gaining access to the vascular lumen.
ae
Human tissues are organized into a series of compartments separated from each other by
two types of extracellular matrix: basement membranes and interstitial connective tissue.
a
Although organised differently, each type of ECM
is composed of collagens,
glycoproteins, and proteoglycans.
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Tumour cells must interact with the ECM at several stages in the metastatic cascade.
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This process is repeated in reverse when tumour cell emboli extravasate at a distant site.
1- Loosening of intercellular connections between tumour cells.
2- Local degradation of the basement membrane and interstitial connective tissue.
Tumour cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g.,
fibroblasts and inflammatory cells) to elaborate proteases.
3- Changes in attachment of tumour cells to ECM proteins. Cleavage of the basement membrane
proteins, collagen IV, and laminin by matrix metalloproteinase-2 or MMP-9 generates novel sites
that bind to receptors on tumour cells and stimulate migration.
4- Locomotion (migration) is the final step of invasion.
Metastasis (distant spread)
(1)- Tumour cell loosening
In epithelial cancers, there is either loss or inactivation of E-cadherin (cell adhesion molecule)
and other cell adhesion molecules.
(2)- Tumour cell-ECM interaction (attachment)
Malignant cells attach to ECM proteins (mainly laminin and fibronectin).
(3)- Degradation of ECM (invasion of the basement membrane)
Tumour cells overexpress proteases and matrix-degrading enzymes, metalloproteinases (e.g.,
collagenases and gelatinase), while the inhibitors of metalloproteinases are decreased.
(4)- Entry of tumour cells into capillary lumen
The tumour cells degrade the vascular basement membrane and migrate into lumen of capillaries
or venules.
(S)- Thrombus formation
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The tumour cells protruding in the lumen of the capillary are now covered with constituents of
the circulating blood and form the thrombus.
(6)- Extravasation of tumour cells
Tumour cells in the circulation (capillaries, venules, lymphatics) may mechanically block these
vascular channels and attach to vascular endothelium and then extravasate to the extravascular
space.
(7)- Survival and growth of metastatic deposit
The extravasated malignant cells on lodgement in the right environment grow further. Metastatic
deposits may further metastasise to the same organ or to other sites by forming emboli.
The site at which metastases appear is related to two factors:
1- The anatomical location and vascular drainage of the primary tumour.
Most metastases occur in the first capillary bed available to the tumour, hence the frequency of
metastases to liver and lung.
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Emboli detached from primary tumours of organs e.g., kidney, brain, breast drained by
systemic veins causing lung metastases through pulmonary arteries.
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Emboli detached from primary tumours of lungs causing metastases in different organs
through pulmonary veins.
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Emboli detached from tumours of organs drained by portal veins (tumours of GIT) causing
liver metastases.
2- Tropism of particular tumours for specific tissues.
Summary
hallmark ofmalignancy,
Ability to invade tissues, a
1- Loosening of cell-cell contacts
2- Degradation of ECM
3- Attachment to novel ECM _ components
4- Migration
of tumour cells
occurs
in four
steps:
* Basement membrane and interstitial matrix degradation is mediated by proteolytic enzymes
secreted by tumour cells and stromal cells.
* Proteolytic enzymes
also release growth factors sequestered in the ECM and generate
chemotactic and angiogenic fragments from cleavage of ECM
glycoproteins.
* The metastatic site of many tumours can be predicted by the location of the primary
tumour.
* any tumours
arrest in the first capillary
bed
they — encounter
(lung and
liver,
most commonly).
* Some
tumours
show
organ tropism, probably due to activation of adhesion or
chemokine receptors whose ligands are expressed by endothelial cells at the metastatic
Site.