(A) Cells that are not proliferating will normally oxidize nearly all of the glucose that they import from the blood to produce ATP through the oxidative phosphorylation that takes place in their mitochondria. Only when deprived of oxygen will these cells generate most of their ATP from glycolysis, converting the pyruvate produced to lactate in order to regenerate the NAD+ that they need to keep glycolysis going (see Figure 2–47). (B) Tumor cells, by contrast, will generally produce abundant lactate even in the presence of oxygen. This results from a greatly increased rate of glycolysis that is fed by a very large increase in the rate of glucose import. In this way, tumor cells resemble the rapidly proliferating cells in embryos (and during tissue repair), which likewise require for biosynthesis a large supply of the small-molecule building blocks that can be produced from imported glucose (see also Figure 20–26).
1100 Chapter 20: Cancer after a certain number of population doublings (25–50 for human fibroblasts, for example). This cell-division-counting mechanism is termed replicative cell senescence, and it generally depends on the progressive shortening of the telomeres at the ends of chromosomes, a process that eventually changes their structure (discussed in Chapter 17). As discussed in Chapter 5, the replication of telomere DNA during S phase depends on the enzyme telomerase, which maintains a special telomeric DNA sequence that promotes the formation of protein cap structures to protect chromosome ends. Because many proliferating human cells (stem cells being an exception) are deficient in telomerase, their telomeres shorten with every division, and their protective caps deteriorate, creating a DNA damage signal. Eventually, the altered chromosome ends can trigger a permanent cell-cycle arrest, causing a normal cell to die.
Human cancer cells avoid replicative cell senescence in one of two ways. They can maintain the activity of telomerase as they proliferate, so that their telomeres do not shorten or become uncapped, or they can evolve an alternate mechanism based on homologous recombination (called ALT) for elongating their chromosome ends. Regardless of the strategy used, the result is that the cancer cells continue to proliferate under conditions when normal cells would stop.
The Tumor Microenvironment Influences Cancer Development
While the cancer cells in a tumor are the bearers of dangerous mutations and are often grossly abnormal, the other cells in the tumor—especially those of the supporting connective tissue, or stroma—are far from passive bystanders. The
Figure 20–13Both increased cell division and decreased apoptosis can contribute to tumorigenesis. In normal tissues, apoptosis balances cell division to maintain homeostasis (see Movie 18.1). During the development of cancer, either an increase in cell division or an inhibition of apoptosis can lead to the increased cell numbers important for tumorigenesis. The cells fated to undergo apoptosis are gray in this diagram. Both an increase in cell division and a decrease in apoptosis normally contribute to tumor growth.
Figure 20–14Cross-section of a colon adenocarcinoma that has metastasized to the lung. This tissue slice shows well-differentiated colorectal cancer cells forming cohesive glands in the lung. The metastasis has central pink areas of necrosis where dying cancer cells have outgrown their blood supply. Such anoxic regions are common in the interior of large tumors. (Courtesy of Andrew J. Connolly.) development of a tumor relies on a two-way communication between the tumor cells and the tumor stroma, just as the normal development of epithelial organs relies on communication between epithelial cells and mesenchymal cells (discussed in Chapter 22).