All cells in the body at every moment are subject to the dynamic balance that exists between pro-life and pro-death signals. Two very basic pro-life signals are "do not die" and "do proliferate"; their counterpart pro-death signals are "do die" and "do not proliferate." All of these signals exist more or less simultaneously, and their relative strengths decide a cell's fate. Of these signals, "do die" and "do not proliferate" seem to be the defaults. That is, if cells are not told to live, they will undergo apoptosis, and if they are not told to proliferate, they will not enter the cell cycle.
The signals that tell a cell to live or to proliferate generally come from outside the cell, commonly from contact with growth factors and from contact, or lack of it, with other cells and tissues. To illustrate how these signals occur in normal tissues, consider the liver tissue of a healthy animal. The liver cells are in close contact with one another, both through actions of cell adhesion molecules on the surface of the cells and through gap junctions (portals) between cells. The liver cells do not undergo apoptosis, since contact with neighboring cells continually generates "do not die" signals. Also, they do not enter the cell cycle because there are few "do proliferate" signals.
Now imagine that the animal receives an injury that slices away a small section of its liver. The injured area soon becomes inflamed and steeped in growth factors. These factors, produced by immune cells, released from the blood, or derived from other sources, cause various types of cells to proliferate. For example, blood vessel cells proliferate to replace those damaged in the injury, and liver cells are also stimulated to proliferate by these growth factors. In addition, the reduced cell-to-cell contact at the edge of the healthy liver tissue signals that new liver cells are needed. In response to the growth factors and signals from reduced cell-to-cell contact, stem cells or other poorly differentiated cells in the liver enter the cell cycle and proliferate. The entire repair process and all the cell proliferation that goes on in it is wondrously orchestrated so that once tissue repair is complete, no new tissue is produced.
I stated previously that cell-to-cell contact is needed to generate "do not die" signals, but above I state that liver cells are stimulated to proliferate by lack of cell-to-cell contact. This apparent contradiction can be explained by considering that the growth factors present at the wound site provide signals that both stimulate proliferation and mimic the "do not die" signals normally originating from cell-to-cell contact. In addition, the liver cells at the edge of the injury are only partially separated from other liver cells.
The situation with cancer cells is both like and unlike the example of injured liver tissue. It is similar in that cancer cells, like liver cells, are stimulated to proliferate and not to undergo apoptosis. It is different in that the proliferation of cancer cells continues indefinitely. Moreover, the sources of "do proliferate" and "do not die" signals are also somewhat different. In both cases, inflammation results in the production or release of
Figure 4.1 Plasma Membrane outside of cell outside of cell
molecule proteins receptor protein
Inside of cell growth factors, but in cancer, the cells themselves also produce their own growth factors. In addition, cancer cells can get the most out of any available growth factors by producing excessive amounts of both the growth factor receptors and the proteins needed in signal trans-duction.
Cancer cells differ from injured liver cells in other ways. For one thing, cancer cells are generally less differentiated than liver cells. Since poorly differentiated cells are prone to proliferate, a relatively large population of cancer cells can enter the cell cycle in response to growth factor activity and signal transduction. In addition, oncogenes within cancer cells can directly produce proteins such as fos and jun that initiate the cell cycle, and ones such as cyclins that drive the cell cycle proper. Oncogenes are not overexpressed in liver cells.
Lastly, other gene derangements in cancer cells can lead to overproduction of proteins that protect against apoptosis (such as Bcl-2) and can lead to malfunctions or underproduction of proteins that induce apoptosis (such as p53 and Bax). These abnormalities do not occur in liver cells.
All the above factors allow cancer cells to override the complex controls that normally govern proliferation and survival. We can draw the analogy between cancerous and injured tissues; the environments of both allow increased cell proliferation, but the former acts as a wound that does not heal, and so its cell population expands without the limits inherent in the final stages of normal healing.
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