Metastasis

The danger of cancer lies in the ability of its cells to spread throughout the body

It is the ability of certain cancer cells to metastasize—to spread throughout the body—that makes them life-threatening. Not all cancer cells have the ability to spread; there are myriad changes a cancer cell must go through to become metastatic, and relatively few cells succeed in doing so. The process is remarkably complex: the metastatic cell must break away from tumor mass, burrow through the wall of a blood vessel or lymphatic vessel, travel to a distant site, move through the vessel wall, establish itself in a new area, and proliferate, thereby forming a new tumor.

At several points during the journey the cell must penetrate a basement membrane. The basement membrane (basal lamina) is an extracellular layer of material that separates epithelial (surface) tissue from the underlying connective tissue. Such membranes are reinforced by a complex of proteins, which serve as a mechanical barrier to contain the growth of tumors. To penetrate the barrier, the cancerous cell produces special membrane receptors that allow it to bind to portions of the basement membrane. The cell then secretes enzymes that digest the basement membrane, which allows the cell to cross the barrier.

A crucial step in metastasis is the ability of a tumor cell to cross the basement membrane. The basement membrane is an extracellular layer of material that separates surface tissue from the underlying connective tissue. In particular, the capacity to break through the basement membrane surrounding blood vessels allows cancer cells to spread throughout the body. Such membranes serve as mechanical barriers that contain the growth of tumors. To penetrate the barrier, the cancerous cell produces special membrane receptors that allow the cell to bind to proteins of the basement membrane; the cell then secretes enzymes that digest the basement membrane (A) and allows the cell to cross the barrier (B).

In particular, cancer cells that break through the basement membrane surrounding blood capillaries may spread throughout the body. However, they face additional obstacles. Once the cells have reached the lymphatic vessels or bloodstream, they become the target of the host defenses, the cells of the immune system. Most cancerous cells probably die as a result of the immune attack, but a few may penetrate a vessel wall and invade a new area. Many of the metastatic cells land in a nearby lymph node or capillary bed, but often they enter the general circulation and pass through the heart, frequently ending up in the capillaries of the lungs. Many of the cells that arrive at the new site will not be able to grow there, however. Cancer cells have sometimes been likened to plant seeds—just as seeds can grow only when they are planted in appropriate soil, so cancer cells can grow only if they reach hospitable “soil”—that is, if the proper growth factors or hormones are present. The process of metastasis is so difficult that it is estimated that fewer than one cell in 10,000 has the ability to leave the primary tumor and successfully establish a secondary tumor in a new area.

Metastasis of cancer cells. Some cancer cells are noninvasive; they multiply and grow but lack the ability to penetrate the basement membrane (A). Such cells simply pile up in the area above the basement membrane. Some cancer cells, on the other hand, have the ability to penetrate the membrane (B). If such cells penetrate the basement membrane in a blood vessel, they can enter the bloodstream and travel to distant sites.

Development of a malignant tumor. Normal tissue has differentiated cells with small, quiescent nuclei, separated from the circulatory system and loosely packed connective tissue by a tough basement membrane (A). When a cell incurs enough changes to begin proliferating, its nucleus enlarges, its shape changes, and it begins to replicate its DNA. As the cell reproduces, the clone it forms begins to push other cells back. If it lacks contact inhibition, it will grow regardless of crowding, and if it is not limited to a fixed number of divisions, the clone will grow as long as nutrients (blood supply) permit, but may still be contained by the basement membrane (B). If a cell in the clone develops the ability to penetrate the basement membrane, it will create a breach and its descendants will move across and proliferate. The tumor will metastasize widely when it penetrates the basement membrane surrounding blood vessels (C). A new tumor can form at a secondary site as the metastatic cell penetrates the blood vessel in a new area (D).

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