In normal tissues, cell proliferation is a tightly controlled process. Growth-promoting factors are released in a highly controlled fashion to ensure that cells proliferate only to replenish a tissue. Cancer cells have evolved mechanisms to escape these tight controls. As will be discussed in detail in Section 24.4, cancer cells up-regulate growth-promoting pathways while simultaneously down-regulating growth-inhibiting and cell death pathways. In this manner, cancer cells gain the ability to proliferate continuously. This ability leads to the expansion of the cancer cell population. As we will see, selective targeting of the mutations that cause uncontrolled proliferation is a highly successful approach in treating certain types of cancers.
Increases in proliferation-promoting signals and decreases in proliferation-inhibiting signals are not the only changes that endow cancer cells with the ability to proliferate indefinitely. Chromosome ends need to be protected throughout cancer cell proliferation. Telomeres, the physical ends of linear chromosomes (discussed in Chapter 8), consist of tandem arrays of a short DNA sequence, TTAGGG in vertebrates. Telomerase, a reverse transcriptase that contains an RNA template, repeatedly adds TTAGGG repeats to chromosome ends to lengthen or maintain the 3–20-kb regions of repeats that decorate the ends of human chromosomes. Embryonic cells, germ-line cells, and stem cells produce telomerase, but most human somatic cells produce only a small amount of telomerase as they enter S phase. As a result of their modest telomerase activity, their telomeres shorten with each cell cycle. Extensive shortening of telomeres is recognized by the cell as a double-strand break and consequently triggers cell cycle arrest and apoptosis. Tumor cells overcome this fate by producing telomerase. Many researchers believe that telomerase expression is essential for a tumor cell to become immortal. Indeed, the introduction of telomerase-producing transgenes into cultured human cells that otherwise lack the enzyme can extend their life span by more than 20 doublings while maintaining telomere length. The reliance of many cancers on increased telomerase activity has led some researchers to propose that inhibitors of telomerase could be highly effective cancer therapeutic agents.