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CHAPTER 24

Cancer

Cancer causes about one-fifth of the deaths in the United States each year. Worldwide, between 100 and 350 of every 100,000 people die of cancer each year. Cancer results from failures of the mechanisms that usually control the growth and proliferation of cells. During normal development and throughout adult life, intricate genetic control systems regulate the balance between cell birth and cell death in response to growth signals, growth-inhibiting signals, and death signals. Cell birth and death rates determine the rate of growth and adult body size. In some adult tissues, cell proliferation occurs continuously as a constant tissue-renewal strategy. Intestinal epithelial cells, for instance, live for just a few days before they die and are replaced; certain white blood cells are replaced just as rapidly, and skin cells commonly survive for only 2–4 weeks before being shed. The cells in many adult tissues, however, normally do not proliferate except during healing processes. Such stable cells (e.g., hepatocytes, heart muscle cells, neurons) can remain functional for long periods or even for the entire lifetime of an organism. Cancer occurs when the mechanisms that maintain normal proliferation rates malfunction to cause excess cell division.

The losses of cellular regulation that give rise to most or all cases of cancer result from genetic damage that is often caused by tumor-promoting chemicals, hormones, and sometimes viruses. Mutations in three broad classes of genes have been implicated in the onset of cancer. Proto-oncogenes normally promote cell growth; mutations change them into oncogenes whose products are excessively active in growth promotion. Oncogenic mutations usually result in either increased gene expression or production of a hyperactive gene product. Tumor-suppressor genes normally restrain growth, so mutations that inactivate them allow inappropriate cell division. A third class of genes often linked to cancer, called genome maintenance genes, are involved in maintaining the genome’s integrity. When these genes are inactivated, cells acquire additional genetic changes at an increased rate—including mutations that cause the deregulation of cell growth and proliferation and lead to cancer. Many of the genes in these three classes encode proteins that help regulate cell proliferation (i.e., entry into and progression through the cell cycle) or cell death by apoptosis; others encode proteins that participate in repairing damaged DNA.

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The cancer-forming process, called oncogenesis or tumorigenesis, is an interplay between genetics and the environment. Most cancers arise after genes are altered by cancer-causing chemicals, known as carcinogens, or by errors in their copying and repair. Even if the genetic damage occurs in only one somatic cell, division of this cell will transmit the damage to its daughter cells, giving rise to a clone of altered cells. Rarely, however, does mutation in a single gene lead to the onset of cancer. More typically, a series of mutations in multiple genes creates a progressively more rapidly proliferating cell type that escapes normal growth restraints, creating an opportunity for additional mutations. The cells also acquire other properties that give them an advantage, such as the ability to escape from normal epithelia and to stimulate the growth of vasculature to obtain oxygen. Eventually the clone of cells grows into a tumor. In some cases, cells from the primary tumor migrate to new sites, where they form secondary tumors, a process termed metastasis. Most cancer deaths are due to invasive, fast-growing metastasized tumors.

Time plays an important role in cancer. It may take many years for a cell to accumulate the multiple mutations that are required to form a tumor, so most cancers develop later in life. The requirement for multiple mutations also lowers the frequency of cancer compared with what it would be if tumorigenesis were triggered by a single mutation. However, huge numbers of cells are, in essence, mutagenized and tested for altered growth during our lifetimes, a powerful selection in favor of these mutagenized cells, which, in this case, we do not want. Cells that proliferate quickly become more abundant, undergo further genetic changes, and can become progressively more dangerous. Furthermore, cancer occurs most frequently after the age of reproduction and therefore plays little role in reproductive success. So cancer is common, in part reflecting an increasingly longer human life span, but also reflecting the lack of selective pressure against the disease.

Clinically, cancers are often classified by their embryonic tissue of origin. Malignant tumors are classified as carcinomas if they derive from epithelia such as endoderm (gut epithelium) or ectoderm (skin and neural epithelia) and sarcomas if they derive from mesoderm (muscle, blood, and connective tissue precursors). Carcinomas are by far the most common type of malignant tumor (more than 90 percent). Most tumors are solid masses, but the leukemias, a class of sarcomas, grow as individual cells in the blood. (The name leukemia is derived from the Latin for “white blood”: the massive proliferation of leukemic cells can cause a patient’s blood to appear milky.)

In this chapter, we first introduce the properties of tumor cells, illustrating how every aspect of cellular homeostasis and the interaction of cells with their environment is altered in cancer. We then discuss the origins of cancer and describe the evolutionary process that leads to the formation of malignant, often metastatic, cancers. Next we consider the general types of genetic changes that lead to the unique characteristics of cancer cells and the interplay between somatic and inherited mutations. The following section examines in detail how mutations affecting both growth-promoting and growth-inhibiting processes can result in excess cell proliferation. We conclude the chapter with a discussion of the role of cell cycle deregulation in cancer and of how the breakdown of genome maintenance functions contributes to tumorigenesis.