The Biology of Cancer

How Cancer Spreads

How Cancer Spreads: The where, why, and how

The Metastasis Potential of Cancers

Lymph/Blood Chronology of Metastasis

Specificity

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Overview: Metastasis is directed to differene organs depending on the cancer. The pathways for metastasis are the blood and lymphatic circulation.

How Does Cancer Spread to different parts of the body?

• Direct extension: Only in ovarian cancer, central nervous system, and lung, where the cells shed and reattatch elsewhere
• Blood Circulation
• Lymphatic Circulation: This is why lymph nodes are studied to determine whether cancer has spread to other organs

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How often does metastasis happen?

• 30% of cancers have overt metastasis: Cancer spreads to other organs on a finite time line
• 30-40% of cancers appear clinically free of metastasis but occult (hidden) metastasis will appear as new cancers later in life
• 30% of cancers do not appear to metastasize at all, and can be cured by therapy directed only towards the primary site

How soon does metastasis happen?

• Metastasis occurs before the cancer has grown to a detectable size/very soon after inception. Extremely virulent, such as small cell cancer (lung) and undifferentiated tumors of the thyroid
• Metastasis occurs on the basis of size: Larger tumors have a higher chance of metastasis. For example, breast cancer, squamous carcinoma of the lung, and colon cancer
• Metastasis is extremely infrequent/does not happen at all. For example, basal cell carcinoma of the skin

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• Invasion: Cancer cells move from the main tumor into surrounding small venules. This process is known as Intravasation.
  • Loss of tight junction of the epithelial cells
  • Attachment of cells to the basement membrane
  • Dissolution of the basement membrane with hydrolitic enzymes such as collagenase, heparnase, and hyalurionidase
  • Entrance into and locomotion through the Extracellular Matrix, aided by chemotactic enzymes
  • Attachment to and lysis of the Basement Membrane of the capillaries
  • Entrance into the blood vessel
• Embollus formation: Cancer cells travel through the circulatory system until it grows into a small plug. Only 0.01% of cancer cells survive in circulation.
• Arrest in a small vessel. If the vessel is in a preffered site, the cancer cells can go on to extravasculation, otherwise the cells die.
• Extravasculation: Movement out of the vessel into the new organ: This occurs only if the enzymes which the cancer cells make are able to act on the substance of the new organ. This is the basis for the organ-specificity of some cancers.
  • Attachment of cells to the Basement Membrane of the blood vessel
  • Lysis of the Basement Membrane of the blood vessel
  • Locomotion through the Extracellular Matrix aided by chemotactic enzymes
• Growth and vascularization: When the growth reaches about 1,000,000 cells, angiogenesis (the formation of blood vessels) occurs

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• Paget: Seed and Soil Theory. Cells are dispersed randomly but only grow in organs which provide the correct factors necessary for growth of that particular tumor (fertile soil)
• Ewing: Mechanistic Theory. The first site to which a cancer metastasizes is the closest one in which there are small blood vessels.

Several properties of metastatic cells determine tissue specificity.

• Some cancers seem to have a homing ability. Sugarbakers demonstrated this by transplanting a lung-metastasizing cancer into a mouse. Both the actual lungs of the mouse and lung cells which were transplanted under the skin were affected, while spleen cells transplanted under the skin were not affected.
• Cannot destroy Basement Membrane or Extracellular Matrix in some organs (according to which enzymes the cancer cells express)
• Tumor cells have specific attachment to endothelial cells: Experiments have shown that lung-metastasizing cancer cells adhere better to cultures of lung endothelial cells than to other endothelial cells.
• Only some organs have the right growth factors for a particular cancer

How does specificity come about?

• CD44 is associated with homing of lymphocytes. Panceatic tumors which have a CD44 variant that is not present in normal pancratic cells are unable to metastasize. Transfection of the normal CD44 gene sometimes allows this tumor to begin metsastasis.
  • expressed in lymphocytes and epithelial cells
  • glycoprotein with many variations
  • Have homing ability for specific lymph nodes
• NM23 is 10x higher in low metastatic clones. Highly metastatic cancers have low levels of NM23 gene products expressed.

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