Chapter 9 Metastasis
Introduction
Metastasis: tumor cells from a primary site invade and migrate to other parts of the
body
Organs have boundaries (basement membranes); made up of
extracellular matrix proteins:
1. Laminins
2. Type IV collagen
3. Proteoglycans
The spread of cells throughout the body results in:
1. Physical obstruction of the target organ
2. Competition with normal cells for nutrients and oxygen
3. Invasion and interference with organ function
Organotropism: specific cancers
metastasize to particular sites
Prostate cancer: metastasize to
especially bone marrow
Colon cancer: metastasize to
especially liver
Breast cancer: metastasize to
especially bone marrow
Pancreas cancer: metastasize to especially liver
This can be explained by:
1. Directionality of the blood flow (James Eweing, 1930) -- organs in close
proximity “en route” are likely to be main sites of metastasis
2. ‘Seed and soil’ theory (Paget, 1889) – cancer cells are seeds that require a
match with optimal environment or ‘soil’ to succeed.
This theory is supported by metastatic nich: a site of further metastasis that is
altered in preparation for the arrival of tumor cells.
The primary tumor itself prepares the distant ‘soil’ or tumor microenvironment
(tumor-associated stroma) via tumor-secreted factors
Tumors spread
Tumors are heterogeinity and thus consist of multiple subclones with:
Different mutations
Different epigenetic alterations
Spreading can be:
Monoclonal linear: being seeded by one subclone
+ from primary tumor to metastasis
Monoclonal branched; being seeded by one
subclone + with one primary tumor seeding two or
more other metastasis
Polyclonal linear; being seeded by 2 or more
subclones + + from primary tumor to metastasis
, Polyclonal branched; being seeded by 2 or more subclones + with one primary
tumor seeding two or more other metastasis
Cross seeding; metastases can be seeded not only from cells of the primary
tumor but also from subclones from other metastases
The process of metastasis
1. Invasion
2. Intravasation
3. Transport (via blood, lymph)
4. Extravasation
5. Metastatic colonization
6. Angiogenesis
Watch out: not every cell from the primary tumor is able to
metastasize. Complex interactions between primary tumor
cells and the tumor-associated stroma affect the ability of individual cells to
metastasize.
Invasion -- cells of the primary tumor need to invade into their local environment
Signals from the tumor stroma (growth factors HGF, EGF, PDGF)
induce EMT (epithelial-mesenchymal transition) in neighbouring
tumor cells via their specific receptors (kinase receptors) this
activates transcription factors (Twist, snail, slug, Zeg1) that control
sets of genes (N-cadherin) needed to trigger EMT EMT
facilitates motility and invasion into the stroma (conversion of
closely connected epithelial cells into highly mobile mesenchymal
cells)
This process of EMT is reversible!
Tools of invasion:
Cell-adhesion molecules (CAM) (E-cadherin);
contract cell-cell contact
They keep cells in place; cadherins are calcium-
dependent transmembrane glycoproteins that interact
via catenins with cytoskeleton.
E-cadherin act as a tumor suppressor – it secure cell-
cell adhesion and suppresses metastasis.
During EMT E-cadherin is down-regulated – cell-cell
adhesion is gone
How do we know? Anti-E-cadherin antibody
treatment resulted in invasive behaviour because there is no cell-cell adhesion
anymore.
Transfection of E-cadherin cDNA/ORF in metastatic epithelial cells can render
them non-invasive reversible!
Introduction
Metastasis: tumor cells from a primary site invade and migrate to other parts of the
body
Organs have boundaries (basement membranes); made up of
extracellular matrix proteins:
1. Laminins
2. Type IV collagen
3. Proteoglycans
The spread of cells throughout the body results in:
1. Physical obstruction of the target organ
2. Competition with normal cells for nutrients and oxygen
3. Invasion and interference with organ function
Organotropism: specific cancers
metastasize to particular sites
Prostate cancer: metastasize to
especially bone marrow
Colon cancer: metastasize to
especially liver
Breast cancer: metastasize to
especially bone marrow
Pancreas cancer: metastasize to especially liver
This can be explained by:
1. Directionality of the blood flow (James Eweing, 1930) -- organs in close
proximity “en route” are likely to be main sites of metastasis
2. ‘Seed and soil’ theory (Paget, 1889) – cancer cells are seeds that require a
match with optimal environment or ‘soil’ to succeed.
This theory is supported by metastatic nich: a site of further metastasis that is
altered in preparation for the arrival of tumor cells.
The primary tumor itself prepares the distant ‘soil’ or tumor microenvironment
(tumor-associated stroma) via tumor-secreted factors
Tumors spread
Tumors are heterogeinity and thus consist of multiple subclones with:
Different mutations
Different epigenetic alterations
Spreading can be:
Monoclonal linear: being seeded by one subclone
+ from primary tumor to metastasis
Monoclonal branched; being seeded by one
subclone + with one primary tumor seeding two or
more other metastasis
Polyclonal linear; being seeded by 2 or more
subclones + + from primary tumor to metastasis
, Polyclonal branched; being seeded by 2 or more subclones + with one primary
tumor seeding two or more other metastasis
Cross seeding; metastases can be seeded not only from cells of the primary
tumor but also from subclones from other metastases
The process of metastasis
1. Invasion
2. Intravasation
3. Transport (via blood, lymph)
4. Extravasation
5. Metastatic colonization
6. Angiogenesis
Watch out: not every cell from the primary tumor is able to
metastasize. Complex interactions between primary tumor
cells and the tumor-associated stroma affect the ability of individual cells to
metastasize.
Invasion -- cells of the primary tumor need to invade into their local environment
Signals from the tumor stroma (growth factors HGF, EGF, PDGF)
induce EMT (epithelial-mesenchymal transition) in neighbouring
tumor cells via their specific receptors (kinase receptors) this
activates transcription factors (Twist, snail, slug, Zeg1) that control
sets of genes (N-cadherin) needed to trigger EMT EMT
facilitates motility and invasion into the stroma (conversion of
closely connected epithelial cells into highly mobile mesenchymal
cells)
This process of EMT is reversible!
Tools of invasion:
Cell-adhesion molecules (CAM) (E-cadherin);
contract cell-cell contact
They keep cells in place; cadherins are calcium-
dependent transmembrane glycoproteins that interact
via catenins with cytoskeleton.
E-cadherin act as a tumor suppressor – it secure cell-
cell adhesion and suppresses metastasis.
During EMT E-cadherin is down-regulated – cell-cell
adhesion is gone
How do we know? Anti-E-cadherin antibody
treatment resulted in invasive behaviour because there is no cell-cell adhesion
anymore.
Transfection of E-cadherin cDNA/ORF in metastatic epithelial cells can render
them non-invasive reversible!
