TUMOR METASTASIS
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Definition: Metastasis is spread of tumor by implantation of tumor cells at different sites which is discontinuous with the primary tumor
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It is an important feature of malignant tumors. Benign tumors never metastasize
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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
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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
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Loosening or detachment of tumor cells
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Degradation of basement membrane and interstitial matrix
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Tumor cell interaction with extracellular matrix proteins
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Migration of tumor cells through the degraded extracellular matrix into vascular lumen
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Dissemination of tumor cells through vascular channels
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Homing of the tumor cells
1. Loosening or detachment of the tumor cells
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Epithelial cells are held tightly by the adhesion molecules (eg. E-cadherin) which also help to pass the signals between the cells
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Alterations in these adhesion molecules leads to detachment of the cells.
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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
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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.
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The proteolytic enzymes secreted are
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Metalloproteinases
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Cathepsin D
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Urokinase
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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
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Some cleavage products of ECM (like collagen and proteoglycans) have chemotactic affect for the tumor cell migration
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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
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Epithelial cells have molecules like integrins at the basal surface by which they adhere to the basement membrane laminin and collagen.
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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
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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
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Movement of the tumor cell in specific direction is stimulated by certain factors like
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Tumor cell derived cytokines (autocrine effect)
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Cleavage products of ECM components like collagen and laminin
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Growth factors like IGF –I & II
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Hepatocyte growth factor / scatter factor produced by stromal cells (paracrine effect)
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Tumor cells invade the vessel wall by degrading the wall with proteolytic enzymes.
5. Dissemination of tumor cells through vascular channels
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In the circulation tumor cells are destroyed by various mechanisms like
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Mechanical shear stress
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Apoptosis stimulated by loss of adhesion
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Innate and adaptive immune defenses
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Circulating tumor cells aggregate to form clumps (homeotypic adhesion) and with other blood cells particularly platelets (Heterotypic adhesion)which favours tumor cell survival
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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
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Homing of the tumor cell at metastatic site depends on
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Location of primary tumor
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Vascular drainage of the tumor
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Tropism of particular tumors for specific tissues
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Organ tropism of tumor cells may be due to
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Tumor cells have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organs
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Some tumors exhibit chemokine receptors (eg. CXC4 and CCR7) which determine the target tissue
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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.
Molecular genetics for the metastasis development
All the tumors does not metastasize but only some tumors metastasize. To explain this variability several theories were proposed
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Clonal evolution – mutations accumulate in genetically unstable cancer cells and the tumor becomes heterogenous. Later subclones of tumor cells have the patterns of gene expression that favor the metastasis.
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Tumor cells having metastatic signature of gene expression show predilection for metastasis
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Metastatic signature genes are necessary but not sufficient for metastasis. Additional mutations are required for metastasis
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The capacity of the tumor cells to metastasize involves not only the intrinsic property of tumor cells, but also the characteristic of microenvironment like components of stroma, presence of immune cells and angiogenesis
For metastasis some metastatic oncogenes and metastatic tumor suppressor genes are thought to be involved.
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Metastatic tumor suppressor gene are genes that when lost leads to metastasis. Atleast 12 genes are found to be lost in metastatic lesions and are considered to metastatic tumor suppressor genes.
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Metastatic oncogene are SNAIL and TWIST which encode transcription factors whose primary function is epithelial to mesenchymal transition (EMT). In EMT carcinoma cells down regulate epithelial markers like E-cadherin and upregulate certain mesenchymal markers (eg. Vimentin and smooth muscle actin). SNAIL and TWIST are transcription repressors that downregulate E-cadherin expression.
PATHWAYS OF SPREAD
Dissemination of tumor occurs through the following pathways
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Lymphatic spread
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Hematogenous spread
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Transcoelomic spread
Lymphatic spread
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This is common pathway for the dissemination of carcinomas (rarely sarcomas also). Eg. Breast carcinoma, colonic carcinoma.
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Tumors does not contain functional lymphatics but the lymphatic vessels located at the periphery are sufficient to cause lymphatic spread.
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Pattern of lymph node involvement follows the natural routes of lymphatic drainage
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In some cases local lymphnodes may be bypassed (Skip metastasis) because of venous lymphatic anastomoses or because of inflammation or radiation obliterating lymphatic channels
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“Sentinel lymph node” biopsy is often used to assess presence or absence of metastasis to lymph nodes
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Sentinel lymph node is defined as the first node in a regional lymphatic basin that receives the lymph flow from primary tumor
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Sentinel lymph node mapping can be done by injecting radiolabeled tracers and blue dyes. Frozen section is done and lymph node status is examined to give the opinion to surgeon during surgery.
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Lymph nodes may also act as barrier for tumor spread for minimum time as tumor cells may be destroyed by tumor specific immune response
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Draining nodes may be enlarged due to
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Spread of tumor cells and growth
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Reactive hyperplasia
Hematogenous spread
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This is common mode of spread by sarcomas (also by carcinomas). Eg. Leiomyosarcoma, fibrosarcoma.
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Arteries have thicker wall than veins and hence hematogenous spread occurs through veins.
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Arterial spread occurs when tumor cells pass through pulmonary capillary bed or pulmonary arteriovenous shunts
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In the venous invasion tumor cells come to rest at first capillary bed they come across while
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Commonly liver and lungs are involved, as the portal area drainage flows to liver and all the caval flows to the lungs.
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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.
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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.
Transcoelomic spread
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When the tumor penetrates the surface of the organ it leads to seeding of the cavities and surfaces.
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Most commonly peritoneal cavity is involved.
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Other cavities involved are pleural, pericardial, subarachnoid and joint spaces
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This route is more common in ovarian tumors. Tumor cells are coated on the surface of abdominal viscera and on the peritoneal cavity without infiltrating the organs.
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Other tumors like mucin secreting appendiceal tumors also spread on to the peritoneal surface. The peritoneal cavity is filled with gelatinous mucin and peritoneal surface shows tumor implants. This condition is called “Pseudomyxoma peritonei”
Another route of metastasis is Perineural growth . Eg. Prostatic carcinoma and Gall bladder carcinoma.
References
Robbins Pathologic Basis Disease (8th edition)