The Development and Causes of Cancer

The fundamental abnormality resulting in the development of cancer is the continual unregulated proliferation of cancer cells. Rather than responding appropriately to the signals that control normal cell behavior, cancer cells grow and divide in an uncontrolled manner, invading normal tissues and organs and eventually spreading throughout the body. The generalized loss of growth control exhibited by cancer cells is the net result of accumulated abnormalities in multiple cell regulatory systems and is reflected in several aspects of cell behavior that distinguish cancer cells from their normal counterparts.

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Cancer can result from abnormal proliferation of any of the different kinds of cells in the body, so there are more than a hundred distinct types of cancer, which can vary substantially in their behavior and response to treatment. The most important issue in cancer pathology is the distinction between benign and malignant tumors (Figure 15.1). A tumor is any abnormal proliferation of cells, which may be either benign or malignant. A benign tumor, such as a common skin wart, remains confined to its original location, neither invading surrounding normal tissue nor spreading to distant body sites. A malignant tumor, however, is capable of both invading surrounding normal tissue and spreading throughout the body via the circulatory or lymphatic systems (metastasis). Only malignant tumors are properly referred to as cancers, and it is their ability to invade and metastasize that makes cancer so dangerous. Whereas benign tumors can usually be removed surgically, the spread of malignant tumors to distant body sites frequently makes them resistant to such localized treatment.

Both benign and malignant tumors are classified according to the type of cell from which they arise. Most cancers fall into one of three main groups: carcinomas, sarcomas, and leukemias or lymphomas. Carcinomas, which include approximately 90% of human cancers, are malignancies of epithelial cells. Sarcomas, which are rare in humans, are solid tumors of connective tissues, such as muscle, bone, cartilage, and fibrous tissue. Leukemias and lymphomas, which account for approximately 8% of human malignancies, arise from the blood-forming cells and from cells of the immune system, respectively. Tumors are further classified according to tissue of origin (e.g., lung or breast carcinomas) and the type of cell involved. For example, fibrosarcomas arise from fibroblasts, and erythroid leukemias from precursors of erythrocytes (red blood cells).

Although there are many kinds of cancer, only a few occur frequently (Table 15.1). More than a million cases of cancer are diagnosed annually in the United States, and more than 500,000 Americans die of cancer each year. Cancers of 10 different body sites account for more than 75% of this total cancer incidence. The four most common cancers, accounting for more than half of all cancer cases, are those of the breast, prostate, lung, and colon/rectum. Lung cancer, by far the most lethal, is responsible for nearly 30% of all cancer deaths.

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The Development of Cancer

One of the fundamental features of cancer is tumor clonality, the development of tumors from single cells that begin to proliferate abnormally. The single-cell origin of many tumors has been demonstrated by analysis of X chromosome inactivation (Figure 15.2).

Figure 15.2. Tumor clonality Normal tissue is a mosaic of cells in which different X chromosomes (X1 and X2) have been inactivated. Tumors develop from a single initially altered cell, so each tumor cell displays the same pattern of X inactivation (X1 inactive, X2 active).
As discussed in Chapter 8, one member of the X chromosome pair is inactivated by being converted to heterochromatin in female cells. X inactivation occurs randomly during embryonic development, so one X chromosome is inactivated in some cells, while the other X chromosome is inactivated in other cells. Thus, if a female is heterozygous for an X chromosome gene, different alleles will be expressed in different cells. Normal tissues are composed of mixtures of cells with different inactive X chromosomes, so expression of both alleles is detected in normal tissues of heterozygous females. In contrast, tumor tissues generally express only one allele of a heterozygous X chromosome gene. The implication is that all of the cells constituting such a tumor were derived from a single cell of origin, in which the pattern of X inactivation was fixed before the tumor began to develop.

The clonal origin of tumors does not, however, imply that the original progenitor cell that gives rise to a tumor has initially acquired all of the characteristics of a cancer cell. On the contrary, the development of cancer is a multistep process in which cells gradually become malignant through a progressive series of alterations. One indication of the multistep development of cancer is that most cancers develop late in life. The incidence of colon cancer, for example, increases more than tenfold between the ages of 30 and 50, and another tenfold between 50 and 70 (Figure 15.3). Such a dramatic increase of cancer incidence with age suggests that most cancers develop as a consequence of multiple abnormalities, which accumulate over periods of many years.

At the cellular level, the development of cancer is viewed as a multistep process involving mutation and selection for cells with progressively increasing capacity for proliferation, survival, invasion, and metastasis (Figure 15.4).

Figure 15.4. Stages of tumor development The development of cancer initiates when a single mutated cell begins to proliferate abnormally. Additional mutations followed by selection for more rapidly growing cells within the population then result in progression of the tumor to increasingly rapid growth and malignancy.
The first step in the process, tumor initiation, is thought to be the result of a genetic alteration leading to abnormal proliferation of a single cell. Cell proliferation then leads to the outgrowth of a population of clonally derived tumor cells. Tumor progression continues as additional mutations occur within cells of the tumor population. Some of these mutations confer a selective advantage to the cell, such as more rapid growth, and the descendants of a cell bearing such a mutation will consequently become dominant within the tumor population. The process is called clonal selection, since a new clone of tumor cells has evolved on the basis of its increased growth rate or other properties (such as survival, invasion, or metastasis) that confer a selective advantage. Clonal selection continues throughout tumor development, so tumors continuously become more rapid-growing and increasingly malignant.

Studies of colon carcinomas have provided a clear example of tumor progression during the development of a common human malignancy (Figure 15.5).

Figure 15.5. Development of colon carcinomas A single initially altered cell gives rise to a proliferative cell population, which progresses first to benign adenomas of increasing size and then to malignant carcinoma. The cancer cells invade the underlying connective tissue and penetrate blood and lymphatic vessels, thereby spreading throughout the body.
The earliest stage in tumor development is increased proliferation of colon epithelial cells. One of the cells within this proliferative cell population is then thought to give rise to a small benign neoplasm (an adenoma or polyp). Further rounds of clonal selection lead to the growth of adenomas of increasing size and proliferative potential. Malignant carcinomas then arise from the benign adenomas, indicated by invasion of the tumor cells through the basal lamina into underlying connective tissue. The cancer cells then continue to proliferate and spread through the connective tissues of the colon wall. Eventually the cancer cells penetrate the wall of the colon and invade other abdominal organs, such as the bladder or small intestine. In addition, the cancer cells invade blood and lymphatic vessels, allowing them to metastasize throughout the body.

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Causes of Cancer

Substances that cause cancer, called carcinogens, have been identified both by studies in experimental animals and by epidemiological analysis of cancer frequencies in human populations (e.g., the high incidence of lung cancer among cigarette smokers). Since the development of malignancy is a complex multistep process, many factors may affect the likelihood that cancer will develop, and it is overly simplistic to speak of single causes of most cancers. Nonetheless, many agents, including radiation, chemicals, and viruses, have been found to induce cancer in both experimental animals and humans.

Radiation and many chemical carcinogens (Figure 15.6) act by damaging DNA and inducing mutations. These carcinogens are generally referred to as initiating agents, since the induction of mutations in key target genes is thought to be the initial event leading to cancer development. Some of the initiating agents that contribute to human cancers include solar ultraviolet radiation (the major cause of skin cancer), carcinogenic chemicals in tobacco smoke, and aflatoxin (a potent liver carcinogen produced by some molds that contaminate improperly stored supplies of peanuts and other grains). The carcinogens in tobacco smoke (including benzo(a)pyrene, dimethylnitrosamine, and nickel compounds) are the major identified causes of human cancer. Smoking is the undisputed cause of 80 to 90% of lung cancers, as well as being implicated in cancers of the oral cavity, pharynx, larynx, esophagus, and other sites. In total, it is estimated that smoking is responsible for nearly one-third of all cancer deaths—an impressive toll for a single carcinogenic agent.

Other carcinogens contribute to cancer development by stimulating cell proliferation, rather than by inducing mutations. Such compounds are referred to as tumor promoters, since the increased cell division they induce is required for the outgrowth of a proliferative cell population during early stages of tumor development. The phorbol esters that stimulate cell proliferation by activating protein kinase C (see Figure 13.26) are classic examples. Their activity was defined by studies of chemical induction of skin tumors in mice (Figure 15.7). Tumorigenesis in this system can be initiated by a single treatment with a mutagenic carcinogen. Tumors do not develop, however, unless the mice are subsequently treated with a tumor promoter (usually a phorbol ester) to stimulate proliferation of the mutated cells.

Hormones, particularly estrogens, are important as tumor promoters in the development of some human cancers. The proliferation of cells of the uterine endometrium, for example, is stimulated by estrogen, and exposure to excess estrogen significantly increases the likelihood that a woman will develop endometrial cancer. The risk of endometrial cancer is therefore substantially increased by long-term postmenopausal estrogen replacement therapy with high doses of estrogen alone. Fortunately, this risk is minimized by administration of progesterone to counteract the stimulatory effect of estrogen on endometrial cell proliferation. However, long-term therapy with combinations of estrogen and progesterone may lead to an increased risk of breast cancer.

In addition to chemicals and radiation, some viruses induce cancer both in experimental animals and in humans. The common human cancers caused by viruses include liver cancer and cervical carcinoma, which together account for 10 to 20% of worldwide cancer incidence. These viruses are important not only as causes of human cancer; as discussed later in this chapter, studies of tumor viruses have played a key role in elucidating the molecular events responsible for the development of cancers induced by both viral and nonviral carcinogens.

© 2000 by Geoffrey M. Cooper
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