FEATURE ARTICLE
Metastasis
The spread of cancer cells to distant sites implies a complex series of cellular abnormalities caused, in part, by genetic aberrations
Cornelis J. Van Noorden, Linda Meade-Tollin, Fred Bosman
Circulation
After it has successfully eaten through an organ's connective tissue, the cancer cell makes its way into a nearby blood vessel, squeezing between the endothelial cells lining the vessel lumen to enter the blood vessel itself.
Although the blood vessel provides a conduit for the metastatic cell to reach new tissues, the journey is fraught with peril—only 1 in 10,000 cells survives it. First, there is a large probability the cancer cell will be mechanically destroyed by the stresses that blood cells alone are designed to endure. In addition, the bloodstream is the very place where a cancer cell is likely to encounter the types of white blood cells—such as macrophages and natural killer cells—capable of destroying them, when the cancer cells are recognized as foreign.
Since cancers do take hold in new tissues, they obviously have developed mechanisms for transiting through the bloodstream. For example, they may travel in clusters, increasing the possibility that at least one of them will survive. Or they may surround themselves with blood cells such as platelets, which mask cancer cells from immune surveillance. (Platelets are blood cells involved in clotting.)
Cancer cells that survive the trip through the bloodstream ultimately home in on a new tissue. The selection of the new target is often quite specific to the type of cancer cell. For example, colon-cancer cells have a high affinity for the liver, whereas lung-cancer cells often metastasize to the brain, bones, adrenal glands and pancreas. The choice of target is quite likely determined by very specific interactions between molecules on the cancer-cell surface and molecules on the surfaces of the endothelial cells that line the blood vessels in the new host tissue.
The entire range of specific interactions is not yet known, but it seems likely that carbohydrates protruding from the cancer-cell surface become bound to a type of carbohydrate receptor on the endothelial cells called a selectin. Normally, the carbohydrate-selectin interactions are used by white blood cells that need to identify particular tissues to combat local infection. Apparently cancer cells can exploit this system as well. Each cancer-cell type expresses a different set of carbohydrates on its surface, which would be attracted to different selectin molecules. The specificity of these interactions helps account for the differential homing specificities of different types of cancer cells.
Once the cancer cell contacts a surface to which it can adhere, it rolls along the blood-vessel wall, propelled by the bloodstream, because the carbohydrate-selectin interactions are relatively weak. The cell comes to a complete stop as bonds, mediated by integrins, form between the cells. At this point, the cancer cell enacts a series of events that is almost the reverse of the events that allowed it to leave its primary organ. The cancer cell migrates into the host tissue by passing through the blood-vessel wall and degrading the connective-tissue matrix with proteases. The cancer cell is now ready to proliferate and form a new tumor in its new host tissue.
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