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
Carcinogenesis
A diagnosis of cancer marks an abrupt change in the life of the patient. A line of demarcation has been drawn. Life seems to be separated into before and after. Yet the events that lead a cell to become cancerous take place gradually, sometimes over periods that can exceed 10 years. During this lengthy evolution, cells undergoing cancerous transformation accumulate genetic abnormalities, one important consequence of which is that cellular growth becomes deregulated.
The number of cells in normal tissue is strictly controlled by a system of checks and balances. Cells that are too old, that fail to function properly or that are otherwise no longer needed are programmed to die, a process known as apoptosis. These cells are replaced by new cells, derived from primitive precursors, also called stem cells, that divide and then differentiate into the mature cell type that performs a specific function. In time, these too undergo apoptosis, only to be replaced by younger cells.
Cell death does not take place because a cell just falls apart. Rather it is the result of a carefully controlled genetic program. Given the proper signals, particular genes are activated that encode proteins that carry out the cellular suicide.
Not all cells undergo apoptosis. There is, in fact, a striking variation in the longevity of different cell types. Nerve and muscle cells, for example, are extremely long-lived—if all goes well, they endure for the entire life of the individual. Once these cells reach their fully mature state they can no longer divide, and it is unlikely that there are populations of stem cells that can generate replacements when they die.
Other cells are actually designed to die shortly after reaching maturity. Often these are the cells that turn over frequently, such as skin cells, or the epithelial lining of the digestive system. The epithelial cells lining the digestive tract mucosa live for a maximum of four days after reaching maturity. High-turnover tissues are endowed with a population of stem cells ready to replenish their respective tissues with mature cells, as older cells are sloughed off, used up or eliminated. For example, stem cells in the bone marrow divide continuously to provide sufficient numbers of blood cells. Similarly, the stem cells in the digestive tract are constantly dividing to replace worn-out mucosal epithelial cells.
Some tissues maintain cell-growth rates intermediate between these two extreme scenarios. For example, under normal circumstances, cell division in the liver takes place at a very low rate: At any given time, only one in 10,000 liver cells is dividing. But cell-division rates can be driven up when needed, for instance, to replace cells damaged by viral infection or removed by surgery.
Clearly, then, maintaining the proper number of cells in any tissue requires a delicate balance between cellular production and elimination. Essential to this balance is apoptotic cell loss on one hand and cell division on the other. When an excess of cells is produced by unrestrained cell division, or when too few cells are eliminated by apoptosis, an overabundance of cells accumulates in the tissue. This basically describes the situation in cancer.
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