Figure 20–11 Loss of contact inhibition by cancer cells in cell culture. Most normal cells stop proliferating once they have carpeted the dish with a single layer of cells: proliferation seems to depend on contact with the dish, and to be inhibited by contacts with other cells—a phenomenon known as “contact inhibition.” Cancer cells, in contrast, usually disregard these restraints and continue to grow, so that they pile up on top of one another, as shown (Movie 20.2). (A) Schematic drawing. (B and C) Light micrographs of normal (B) and transformed (C) fibroblasts. (B and C, courtesy of Lan Bo Chen.)
NET PRODUCTS: NET PRODUCTS:
ENERGY, CO2, H2O ENERGY, BUILDING BLOCKS, NADPH effect—so named because Otto Warburg first noticed the phenomenon in the early twentieth century. It is this abnormally high glucose uptake that allows tumors to be selectively imaged in whole-body scans (see Figure 20–1), thereby providing a way to monitor cancer progression and responses to treatment.
Cancer Cells have an Abnormal Ability to Survive Stress and DNA Damage
In a large multicellular organism, there are powerful safety mechanisms that guard against the trouble that can be caused by damaged and deranged cells. For example, internal disorder gives rise to danger signals in the faulty cell, activating protective devices that can eventually lead to apoptosis (see Chapter 18). To survive, cancer cells require additional mutations to elude or break through these defenses against cellular misbehavior.
Cancer cells are found to contain mutations that drive the cell into an abnormal state, where metabolic processes may be unbalanced and essential cell components may be produced in ill-matched proportions. States of this type, where the cell’s homeostatic mechanisms are inadequate to cope with an imposed disturbance, are loosely referred to as states of cell stress. As one example, chromosome breakage and other forms of DNA damage are commonly observed during the development of cancer, reflecting the genetic instability that cancer cells display. Thus, to survive and divide without limit, a prospective cancer cell must accumulate mutations that disable the normal safety mechanisms that would otherwise induce a cell that is stressed, in this or in other ways, to commit suicide. In fact, one of the most important properties of many types of cancer cells is that they fail to undergo apoptosis when a normal cell would do so (Figure 20–13).
While cancer cells tend to avoid apoptosis, this does not mean that they rarely die. On the contrary, in the interior of a large solid tumor, cell death often occurs on a massive scale: living conditions are difficult, with severe competition among the cancer cells for oxygen and nutrients. Many die, but typically much more by necrosis than by apoptosis (Figure 20–14). The tumor grows because the cell birth rate outpaces the cell death rate, but often by only a small margin. For this reason, the time that a tumor takes to double in size can be far longer than the cell-cycle time of the tumor cells.
human Cancer Cells Escape a Built-in Limit to Cell Proliferation
Many normal human cells have a built-in limit to the number of times they can divide when stimulated to proliferate in culture: they permanently stop dividing
Figure 20–12 The Warburg effect in tumor cells reflects a dramatic change in glucose uptake and sugar metabolism.