1.6 Metastasis and Angiogenesis

Описание: Most malignant cells eventually acquire the ability to metastasize
Some malignant tumors, such as those in the ovary or breast, remain localized and encapsulated, at least for a time.

As tumors progress
cells invade surrounding tissues
get into the body’s circulatory system
establish secondary areas of proliferation
This is called metastasis.

What is meant by metastasis?
In some cases cells from the primary tumor migrate to new sites (metastasis), forming secondary tumors that often have the greatest health impact.

Stephen Paget’s paper of 1889 records his careful analyses of case histories

Loss of Attachment
This may occur by mutations in the extracellular domain of the cell adhesion molecule (CAM) E-cadherin causing a loss of attachment between the tumour and its neighbours.
Escaping the extracellular matrix (ECM) and basement membrane
The extracellular matrix and basement membrane are digested via proteases (proteases are secreted to digest the ECM) facilitating invasion into the blood capillary
escape from one location and migration to another.
This is typical for secondary liver and lung cancers

Cells must invade through the basement membrane
Cells must exit the vasculature and establish a new tumour in a foreign microenvironment

Intravasation
cancer cells disseminate to other parts of the body by entering the bloodstream

Extravasation
cancer cells attach to endothelial cells that line blood vessels and cross the vessel walls to enter other tissues or organs.

Successful migration
Successful migration to a new location provides the opportunity for the generation of another tumour
a secondary tumour is thus derived from the primary tumour

This process may occur multiple times leading to various cancer in the body
Cancer cells require some ‘nourishment’ from their environment to develop
Mice injected with radioactive melanoma cells showed that they were equally likely to be trapped in the various tissue but NOT equally likely to form secondary tumours

Some property of the tissue itself must sustain the new growth.
Not all tissue is susceptible to secondary cancer
Tissues under attack are most vulnerable if they produce growth factors and readily grow new vasculature.

They are more resistant if they produce anti-proliferative factors, inhibitors of proteolytic enzymes, and anti-angiogenesis factors.
Tumor Growth Requires Formation of New Blood Vessels
Tumors, whether primary or secondary, require recruitment of new blood vessels in order to grow to a large mass.

In the absence of a blood supply, a tumor can grow into a mass of about 1000,000 cells, roughly a sphere 2 mm in diameter.

Angiogenesis
At this point, division of cells on the outside of the tumor mass is balanced by death of those in the centre due to an inadequate supply of nutrients.

Such tumors cause few problems - unless they secrete hormones that induce the formation of new blood vessels
These vessels invade the tumor and nourish it
This process is called angiogenesis.

Vascular Endothelial Growth Factor (VEGF)
Angiogenesis is a critical process in tumor growth and development.
The predominant regulator of this pathological process is VEGF.
VEGF has been shown to facilitate survival of existing vessels
VEGF is over produced by cancer cells and facilitates improved blood supply to tumor cells