Haematogenous route of metastasis – Histopathology.guru

HAEMATOGENOUS ROUTE OF METASTASIS

Definition: Metastasis is spread of tumor by implantation of tumor cells at different sites which is discontinuous with the primary tumor
It is an important feature of malignant tumors. Benign tumors never metastasize
From the primary tumor many tumor cells are released in the circulation, but only few of them will metastasize and develop the tumors at distant sites
The cells which metastasize will have genetic mutations that predilects them for the metastatic spread. Multiple genetic abnormalities which are responsible for metastasis in a cell are called “metastatic signature”

Invasion and metastasis by tumor cells require sequence of events which are

Loosening or detachment of tumor cells
Degradation of basement membrane and interstitial matrix
Tumor cell interaction with extracellular matrix proteins
Migration of tumor cells through the degraded extracellular matrix into vascular lumen
Dissemination of tumor cells through vascular channels
Homing of the tumor cells

1. Loosening or detachment of the tumor cells

Epithelial cells are held tightly by the adhesion molecules (eg. E-cadherin) which also help to pass the signals between the cells
Alterations in these adhesion molecules leads to detachment of the cells.
In certain tumors like colonic adenocarcinoma, breast and stomach carcinoma E-cadherin expression is lost or downregulated.

2. Degradation of basement membrane and interstitial matrix

Tumor cells secrete proteolytic enzymes. Tumor cells also stimulate other cells like fibroblasts and inflammatory cells to secrete proteolytic enzymes. Degradation of the basement membrane and ECM occurs by these proteolytic enzymes.
The proteolytic enzymes secreted are

Metalloproteinases
Cathepsin D
Urokinase

Matrix metalloproteinases degrade the ECM which also releases certain growth factors like (VEGF) that helps for the angiogenesis and maintenance of blood supply to the tumor mass
Some cleavage products of ECM (like collagen and proteoglycans) have chemotactic affect for the tumor cell migration
In tumors along with increase in proteases there is decrease production of antiproteases which leads to imbalance between protease and antiprotease mechanism leading to ECM degradation.

Degradation of ECM

3. Tumor cell interaction with extracellular matrix proteins

Epithelial cells have molecules like integrins at the basal surface by which they adhere to the basement membrane laminin and collagen.
Loss of adhesions leads to apoptosis in normal cells but in tumor cells apoptosis does not occur instead the modified matrix which have undergone cleavage provides new sites for tumor cell adhesion and stimulates migration

4. Migration of tumor cells through the degraded extracellular matrix into vascular lumen

Epithelial to mesenchymal transition occurs which favours migration
Migration of tumor cells through ECM involves detachment at the distal end, attachment at the leading edge and contraction of cytoskeleton actin to propel the tumor cells forward
Movement of the tumor cell in specific direction is stimulated by certain factors like

Tumor cell derived cytokines (autocrine effect)
Cleavage products of ECM components like collagen and laminin
Growth factors like IGF –I & II
Hepatocyte growth factor / scatter factor produced by stromal cells (paracrine effect)

Tumor cells invade the vessel wall by degrading the wall with proteolytic enzymes.

5. Dissemination of tumor cells through vascular channels

In the circulation tumor cells are destroyed by various mechanisms like

Mechanical shear stress
Apoptosis stimulated by loss of adhesion
Innate and adaptive immune defenses

Circulating tumor cells aggregate to form clumps (homeotypic adhesion) and with other blood cells particularly platelets (Heterotypic adhesion)which favours tumor cell survival
Tumor cells also activate coagulation factors resulting in thrombi and tumor emboli where the tumor cells are covered by blood components which provides protection to tumor cells against the host immune mechanism.

6. Homing of the tumor cells

Homing of the tumor cell at metastatic site depends on

Location of primary tumor
Vascular drainage of the tumor
Tropism of particular tumors for specific tissues

Organ tropism of tumor cells may be due to

Tumor cells have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organs
Some tumors exhibit chemokine receptors (eg. CXC4 and CCR7) which determine the target tissue
Some tissue are unfavorable for growth of tumor cells (eg. skeletal muscle) hence do not have metastatic deposits.

These are few factors for organ tropism though many unknown factors still govern sites for metastatic deposits.

– After reaching the site, extravasation from the vascular channels occur by adhesion of tumor cells to endothelial cells. This process involves adhesion molecules like integrins, laminin and CD44. After adhering to the endothelial cells they secrete proteases which causes vessel wall degradation.

Pathways of tumor metastasis

There are 4 pathways for the metastatic tumor spread. They are-

Hematogenous spread
Lymphatic spread
Transcoelomic spread
Perineural spread

Hematogenous spread

This is common mode of spread by sarcomas (also by carcinomas)
Arteries have thicker wall than veins and hence hematogenous spread occurs through veins.
Arterial spread occurs when tumor cells pass through pulmonary capillary bed or pulmonary arteriovenous shunts
In the venous invasion tumor cells come to rest at first capillary bed they come across
Commonly liver and lungs are involved, as the portal area drainage flows to liver and all the caval flows to the lungs.
Eg. Renal cell carcinoma always invades the renal vein and grows in the vein in a snake like fashion up to the inferior vena cava and sometimes reaching the right heart. Hepatocellular carcinomas often penetrate portal and hepatic veins.
Many tumors does not follow the vascular drainage like breast carcinoma preferentially spreads to bone, bronchogenic carcinoma spreads to adrenals and brain, and neuroblastomas spread to liver and bones. Conversely, skeletal muscles and the spleen despite having large blood circulation are rarely the sites of metastasis.

References

Robbins Pathologic Basis of diseases (8th edition)

Definition: Metastasis is spread of tumor by implantation of tumor cells at different sites which is discontinuous with the primary tumor

It is an important feature of malignant tumors. Benign tumors never metastasize

From the primary tumor many tumor cells are released in the circulation, but only few of them will metastasize and develop the tumors at distant sites

The cells which metastasize will have genetic mutations that predilects them for the metastatic spread. Multiple genetic abnormalities which are responsible for metastasis in a cell are called “metastatic signature”

Invasion and metastasis by tumor cells require sequence of events which are

Loosening or detachment of tumor cells

Degradation of basement membrane and interstitial matrix

Tumor cell interaction with extracellular matrix proteins

Migration of tumor cells through the degraded extracellular matrix into vascular lumen

Dissemination of tumor cells through vascular channels

Homing of the tumor cells

1. Loosening or detachment of the tumor cells

Epithelial cells are held tightly by the adhesion molecules (eg. E-cadherin) which also help to pass the signals between the cells

Alterations in these adhesion molecules leads to detachment of the cells.

In certain tumors like colonic adenocarcinoma, breast and stomach carcinoma E-cadherin expression is lost or downregulated.

2. Degradation of basement membrane and interstitial matrix

Tumor cells secrete proteolytic enzymes. Tumor cells also stimulate other cells like fibroblasts and inflammatory cells to secrete proteolytic enzymes. Degradation of the basement membrane and ECM occurs by these proteolytic enzymes.

The proteolytic enzymes secreted are

Metalloproteinases

Cathepsin D

Urokinase

Matrix metalloproteinases degrade the ECM which also releases certain growth factors like (VEGF) that helps for the angiogenesis and maintenance of blood supply to the tumor mass

Some cleavage products of ECM (like collagen and proteoglycans) have chemotactic affect for the tumor cell migration

In tumors along with increase in proteases there is decrease production of antiproteases which leads to imbalance between protease and antiprotease mechanism leading to ECM degradation.

3. Tumor cell interaction with extracellular matrix proteins

Epithelial cells have molecules like integrins at the basal surface by which they adhere to the basement membrane laminin and collagen.

Loss of adhesions leads to apoptosis in normal cells but in tumor cells apoptosis does not occur instead the modified matrix which have undergone cleavage provides new sites for tumor cell adhesion and stimulates migration

4. Migration of tumor cells through the degraded extracellular matrix into vascular lumen

Epithelial to mesenchymal transition occurs which favours migration

Migration of tumor cells through ECM involves detachment at the distal end, attachment at the leading edge and contraction of cytoskeleton actin to propel the tumor cells forward

Movement of the tumor cell in specific direction is stimulated by certain factors like

Tumor cell derived cytokines (autocrine effect)

Cleavage products of ECM components like collagen and laminin

Growth factors like IGF –I & II

Hepatocyte growth factor / scatter factor produced by stromal cells (paracrine effect)

Tumor cells invade the vessel wall by degrading the wall with proteolytic enzymes.

5. Dissemination of tumor cells through vascular channels

In the circulation tumor cells are destroyed by various mechanisms like

Mechanical shear stress

Apoptosis stimulated by loss of adhesion

Innate and adaptive immune defenses

Circulating tumor cells aggregate to form clumps (homeotypic adhesion) and with other blood cells particularly platelets (Heterotypic adhesion)which favours tumor cell survival

Tumor cells also activate coagulation factors resulting in thrombi and tumor emboli where the tumor cells are covered by blood components which provides protection to tumor cells against the host immune mechanism.

6. Homing of the tumor cells

Homing of the tumor cell at metastatic site depends on

Location of primary tumor

Vascular drainage of the tumor

Tropism of particular tumors for specific tissues

Organ tropism of tumor cells may be due to

Tumor cells have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organs

Some tumors exhibit chemokine receptors (eg. CXC4 and CCR7) which determine the target tissue

Some tissue are unfavorable for growth of tumor cells (eg. skeletal muscle) hence do not have metastatic deposits.

These are few factors for organ tropism though many unknown factors still govern sites for metastatic deposits.

This is common mode of spread by sarcomas (also by carcinomas)

Arteries have thicker wall than veins and hence hematogenous spread occurs through veins.

Arterial spread occurs when tumor cells pass through pulmonary capillary bed or pulmonary arteriovenous shunts

In the venous invasion tumor cells come to rest at first capillary bed they come across

Commonly liver and lungs are involved, as the portal area drainage flows to liver and all the caval flows to the lungs.

Eg. Renal cell carcinoma always invades the renal vein and grows in the vein in a snake like fashion up to the inferior vena cava and sometimes reaching the right heart. Hepatocellular carcinomas often penetrate portal and hepatic veins.

References

Robbins Pathologic Basis of diseases (8th edition)