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Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002.
The body of an animal operates as a society or ecosystem whose individual members are cells, reproducing by cell division and organized into collaborative assemblies or tissues. In our earlier discussion of the maintenance of tissues (Chapter 22), our interests were similar to those of the ecologist: cell births, deaths, habitats, territorial limitations, and the maintenance of population sizes. The one ecological topic conspicuously absent was that of natural selection: we said nothing of competition or mutation among somatic cells. The reason is that a healthy body is in this respect a very peculiar society, where self-sacrifice—as opposed to survival of the fittest—is the rule. Ultimately, all somatic cell lineages are committed to die: they leave no progeny and instead dedicate their existence to support of the germ cells, which alone have a chance of survival. There is no mystery in this, for the body is a clone, and the genome of the somatic cells is the same as that of the germ cells. By their self-sacrifice for the sake of the germ cells, the somatic cells help to propagate copies of their own genes.
Thus, unlike free-living cells such as bacteria, which compete to survive, the cells of a multicellular organism are committed to collaboration. To coordinate their behavior, the cells send, receive, and interpret an elaborate set of signals that serve as social controls, telling each of them how to act (see Chapter 15). As a result, each cell behaves in socially responsible manner, resting, dividing, differentiating, or dying as needed for the good of the organism. Molecular disturbances that upset this harmony mean trouble for a multicellular society. In a human body with more than 1014 cells, billions of cells experience mutations every day, potentially disrupting the social controls. Most dangerously, a mutation may give one cell a selective advantage, allowing it to divide more vigorously than its neighbors and to become a founder of a growing mutant clone. A mutation that gives rise to such selfish behavior by individual members of the cooperative can jeopardize the future of the whole enterprise. Repeated rounds of mutation, competition, and natural selection operating within the population of somatic cells cause matters to go from bad to worse. These are the basic ingredients of cancer: it is a disease in which individual mutant clones of cells begin by prospering at the expense of their neighbors, but in the end destroy the whole cellular society.
In this section we discuss the development of cancer as a microevolutionary process. This process occurs on a time scale of months or years in a population of cells in the body, but it depends on the same principles of mutation and natural selection that govern the long-term evolution of all living organisms.
Cancer cells are defined by two heritable properties: they and their progeny (1) reproduce in defiance of the normal restraints on cell division and (2) invade and colonize territories normally reserved for other cells. It is the combination of these actions that makes cancers peculiarly dangerous. An isolated abnormal cell that does not proliferate more than its normal neighbors does no significant damage, no matter what other disagreeable properties it may have; but if its proliferation is out of control, it will give rise to a tumor, or neoplasm—a relentlessly growing mass of abnormal cells. As long as the neoplastic cells remain clustered together in a single mass, however, the tumor is said to be benign. At this stage, a complete cure can usually be achieved by removing the mass surgically. A tumor is considered a cancer only if it is malignant, that is, only if its cells have acquired the ability to invade surrounding tissue. Invasiveness usually implies an ability to break loose, enter the bloodstream or lymphatic vessels, and form secondary tumors, called metastases, at other sites in the body (Figure 23-1). The more widely a cancer spreads, the harder it becomes to eradicate.
Metastasis. Malignant tumors typically give rise to metastases, making the cancer hard to eradicate. The drawing shows common sites in the bone marrow for metastases from carcinoma of the prostate gland. (From Union Internationale Contre le Cancer, TNM (more...)
Cancers are classified according to the tissue and cell type from which they arise. Cancers arising from epithelial cells are termed carcinomas; those arising from connective tissue or muscle cells are termed sarcomas. Cancers that do not fit in either of these two broad categories include the various leukemias, derived from hemopoietic cells, and cancers derived from cells of the nervous system. Figure 23-2 shows the types of cancers that are common in the United States, together with their incidence and resulting death rate. Each of the broad categories has many subdivisions according to the specific cell type, the location in the body, and the structure of the tumor; many of the names used are fixed by tradition and have no modern rational basis.
Cancer incidence and mortality in the United States. These figures are for the year 2000. Total new cases diagnosed in that year in the United States were 1,220,000, and total cancer deaths were 552,200. Note that only about half the number of people (more...)
In parallel with the set of names for malignant tumors, there is a related set of names for benign tumors: an adenoma, for example, is a benign epithelial tumor with a glandular organization, the corresponding type of malignant tumor being an adenocarcinoma (Figure 23-3); similarly a chondroma and a chondrosarcoma are, respectively, benign and malignant tumors of cartilage. About 90% of human cancers are carcinomas, perhaps because most of the cell proliferation in the body occurs in epithelia, or because epithelial tissues are most frequently exposed to the various forms of physical and chemical damage that favor the development of cancer.
Benign versus malignant tumors. A benign glandular tumor (an adenoma) and a malignant glandular tumor (an adenocarcinoma) appear structurally distinct. There are many forms that such tumors may take; the diagram illustrates types that might be found in (more...)
Each cancer has characteristics that reflect its origin. Thus, for example, the cells of an epidermal basal-cell carcinoma, derived from a keratinocyte stem cell in the skin, will generally continue to synthesize cytokeratin intermediate filaments, whereas the cells of a melanoma, derived from a pigment cell in the skin, will often (but not always) continue to make pigment granules. Cancers originating from different cell types are, in general, very different diseases. The basal-cell carcinoma, for example, is only locally invasive and rarely forms metastases, whereas the melanoma, if not removed promptly, is much more malignant and rapidly gives rise to many metastases (behavior that recalls the migratory tendencies of the normal pigment-cell precursors during development, discussed in Chapter 21). The basal-cell carcinoma is usually easy to remove by surgery, leading to complete cure; but the malignant melanoma, once it has metastasized widely, is often impossible to eliminate and consequently fatal.
Even when a cancer has metastasized, its origins can usually be traced to a single primary tumor, arising in an identified organ and presumed to be derived by cell division from a single cell that has undergone some heritable change that enables it to outgrow its neighbors. By the time it is first detected, however, a typical tumor already contains about a billion cells or more (Figure 23-4), often including many normal cells—fibroblasts, for example, in the supporting connective tissue that is associated with a carcinoma. What evidence do we have that the cancer cells are indeed a clone descended from a single abnormal cell?
The growth of a typical human tumor such as a tumor of the breast. The diameter of the tumor is plotted on a logarithmic scale. Years may elapse before the tumor becomes noticeable. The doubling time of a typical breast tumor, for example, is about 100 (more...)
One clear demonstration of clonal evolution comes from analysis of the chromosomes in tumor cells. Chromosomal aberrations and rearrangements are present in the cells of most common cancers. In almost all patients with chronic myelogenous leukemia, for example, leukemic white blood cells can be distinguished from normal cells by a specific chromosomal abnormality: the so-called Philadelphia chromosome, created by a translocation between the long arms of chromosomes 9 and 22, as shown in Figure 23-5. When the DNA at the site of translocation is cloned and sequenced, it is found that the site of breakage and rejoining of the translocated fragments is identical in all the leukemic cells in any given patient, but differs slightly (by a few hundred or thousand base pairs) from one patient to another, as expected if each case of the leukemia arises from a unique accident occurring in a single cell. We will see later how this Philadelphia translocation leads to leukemia by inappropriately activating a specific gene.
The translocation between chromosomes 9 and 22 responsible for chronic myelogenous leukemia. The smaller of the two resulting abnormal chromosomes is called the Philadelphia chromosome, after the city where the abnormality was first recorded.
Many other lines of evidence, from a variety of cancers, point to the same conclusion: most cancers originate from a single aberrant cell (Figure 23-6).
Evidence from X-inactivation mosaics demonstrates the monoclonal origin of cancers. As a result of a random process that occurs in the early embryo, practically every normal tissue in a woman's body is a mixture of cells with different X chromosomes heritably (more...)
If a single abnormal cell is to give rise to a tumor, it must pass on its abnormality to its progeny: the aberration has to be heritable. A first problem in understanding a cancer is to discover whether the heritable aberration is due to a genetic change—that is, an alteration in the cell's DNA sequence—or to an epigenetic change—that is, a change in the pattern of gene expression without a change in the DNA sequence. Heritable epigenetic changes, reflecting cell memory, occur during normal development, as manifest in the stability of the differentiated state and in such phenomena as X-chromosome inactivation and imprinting (discussed in Chapter 7). Such epigenetic changes have also been found to play a part in the development of some cancers.
There are, however, good reasons to think that the vast majority of cancers are initiated by genetic changes. First, cells of a variety of cancers can be shown to have a shared abnormality in their DNA sequence that distinguishes them from the normal cells surrounding the tumor, as in the example of chronic myelogenous leukemia that we have just described.
Second, many of the agents known to give rise to cancer also cause genetic changes. Thus carcinogenesis (the generation of cancer) appears to be linked with mutagenesis (the production of a change in the DNA sequence). This correlation is clear for three classes of agents: chemical carcinogens (which typically cause simple local changes in the nucleotide sequence), ionizing radiations such as x-rays (which typically cause chromosome breaks and translocations), and viruses (which introduce foreign DNA into the cell). We will discuss each of these agents in detail later, in the section on the preventable causes of cancer.
Finally, the conclusion that somatic mutations underlie cancer is supported by studies of people who inherit a strong susceptibility to the disease. In a significant proportion of cases, the propensity to cancer can be traced to a genetic defect of some sort in the DNA repair mechanisms of these individuals, which allows them to accumulate mutations at an elevated rate. People with the disease xeroderma pigmentosum, for example, have defects in the cellular system that repairs DNA damage induced by UV light, and they experience a hugely increased incidence of skin cancers.
An estimated 1016 cell divisions take place in a normal human body in the course of a lifetime; in a mouse, with its smaller number of cells and its shorter life span, the number is about 1012. Even in an environment that is free of mutagens, mutations will occur spontaneously at an estimated rate of about 10-6 mutations per gene per cell division—a value set by fundamental limitations on the accuracy of DNA replication and repair. Thus, in a lifetime, every single gene is likely to have undergone mutation on about 1010 separate occasions in any individual human being, or about 106 occasions in a mouse. Among the resulting mutant cells one might expect that there would be many that have disturbances in genes that regulate cell division and that consequently disobey the normal restrictions on cell proliferation. From this point of view, the problem of cancer seems to be not why it occurs but why it occurs so infrequently.
Clearly, if a single mutation were enough to convert a typical healthy cell into a cancer cell that proliferates without restraint, we would not be viable organisms. Many types of evidence indicate that the genesis of a cancer typically requires that several independent, rare accidents occur in the lineage of one cell. One such indication comes from epidemiological studies of the incidence of cancer as a function of age (Figure 23-7). If a single mutation were responsible, occurring with a fixed probability per year, the chance of developing cancer in any given year should be independent of age. In fact, for most types of cancer the incidence rises steeply with age—as would be expected if cancer is caused by a slow accumulation of numerous random mutations in a single line of cells. (An additional reason for the increased incidence of cancer in old age is discussed later, when we come to the topic of replicative cell senescence.)
Cancer incidence as a function of age. The number of newly diagnosed cases of colon cancer in women in England and Wales in one year is plotted as a function of age at diagnosis and expressed relative to the total number of individuals in each age group. (more...)
Now that many of the specific mutations responsible for the development of cancer have been identified, we can test directly for their presence in a particular case of the disease. Such tests have revealed that an individual malignant cell generally harbors multiple mutations. Animal models also confirm that a single one of these genetic alterations is insufficient to cause cancer: when genetically engineered in a mouse, a single such mutation typically produces mild abnormalities in tissue growth, followed occasionally by the formation of randomly scattered benign tumors; but the vast majority of cells in the mutant animal remain non-cancerous.
The concept that the development of a cancer requires mutations in many genes—perhaps ten or more—fits with a large body of information, dating back over many years, concerning the phenomenon of tumor progression, whereby an initial mild disorder of cell behavior evolves gradually into a full-blown cancer. As we explain next, these observations of how tumors develop also provide insight into the nature of the changes that must occur for a normal cell to become a cancer cell.
For those cancers that have a discernible external cause, the disease does not usually become apparent until long after exposure to the causal agent: the incidence of lung cancer does not begin to rise steeply until after 10 or 20 years of heavy smoking; the incidence of leukemias in Hiroshima and Nagasaki did not show a marked rise until about 5 years after the explosion of the atomic bombs; industrial workers exposed for a limited period to chemical carcinogens do not usually develop the cancers characteristic of their occupation until 10, 20, or even more years after the exposure (Figure 23-8). During this long incubation period, the prospective cancer cells undergo a succession of changes. The same applies to cancers where the initial genetic lesion has no such obvious external cause.
Delayed onset of cancer following exposure to a carcinogen. The graph shows the length of the delay before onset of bladder cancer in a set of 78 workers in the chemical industry who had been exposed to the carcinogen 2-naphthylamine, grouped according (more...)
Chronic myelogenous leukemia, mentioned earlier, provides a clear and simple example. This disease begins as a disorder characterized by a nonlethal overproduction of white blood cells and continues as such for several years before changing into a much more rapidly progressing illness that usually ends in death within a few months. In the chronic early phase, the leukemic cells in the body are distinguished mainly by their possession of the chromosomal translocation mentioned previously (although there may well be other genetic changes that are not seen so easily). In the subsequent acute phase of the illness, the hemopoietic system is overrun by cells that show not only this chromosomal abnormality but also several others. It appears as though members of the initial mutant clone have undergone further mutations that make them proliferate more rapidly (or divide more times before they die or terminally differentiate), so that they come to outnumber both the normal hemopoietic cells and their relatives that have only the primary chromosomal translocation (the Philadelphia chromosome).
Carcinomas and other solid tumors are thought to evolve in a similar way. Although most such cancers in humans are not diagnosed until a relatively late stage, in a few cases it is possible to observe the early steps in the development of the disease. We shall discuss one example—colorectal cancer—toward the end of this chapter. Another example is provided by cancers of the uterine cervix (the neck of the womb). These cancers are thought to derive from the epithelium near the opening of the cervix.
This epithelium undergoes physiological changes in structure at different times in a woman's reproductive life. In a cervical region liable to give rise to cancer, under the conditions in which the disease originates, the cells are initially organized as a stratified (multilayered) squamous epithelium (Figure 23-9A,E), similar in structure to the epidermis of the skin or the lining of the inside of the mouth (see p. 1274). In such stratified epithelia, proliferation normally occurs only in the basal layer, generating cells that then move out toward the surface; these cells differentiate as they move, forming flattened, keratin-rich, nondividing cells that are sloughed off as they reach the surface. When specimens of cervical epithelium from different women are examined, however, it is not unusual to find patches in which this organization is disturbed in a way that suggests the beginnings of a cancerous transformation. Pathologists describe these changes as intraepithelial neoplasia, and classify them as low-grade (mild) or high-grade (moderate to severe).
The stages of progression in the development of cancer of the epithelium of the uterine cervix. Pathologists use standardized terminology to classify the types of disorder they see, so as to guide the choice of treatment. Schematic diagrams are shown (more...)
In the low-grade lesions, dividing cells are no longer confined to the basal layer but occupy the lower third of the epithelium; although differentiation proceeds in the upper epithelial layers, it is slightly disordered (Figure 23-9B,F). Left alone, most of these mild lesions will spontaneously regress, but a small number (about 10%) may progress to become high-grade lesions. In these more seriously abnormal patches, most or all of the epithelial layers are occupied by undifferentiated dividing cells, which are usually highly variable in cell and nuclear size and shape. Abnormal mitotic figures are frequently seen and the karyotype is usually abnormal, but the abnormal cells are still confined to the epithelial side of the basal lamina (Figure 23-9C,G). The presence of such lesions can be detected by scraping off a sample of cells from the surface of the cervix and viewing it under the microscope (the “Pap smear” technique—Figure 23-10). At this stage, it is still easy to achieve a complete cure by destroying or removing the abnormal tissue surgically.
Photographs of cells collected by scraping the surface of the uterine cervix (the Papanicolaou or “Pap smear” technique). (A) Normal: the cells are large and well differentiated, with highly condensed nuclei. (B) Precancerous lesion: differentiation (more...)
Without treatment, the abnormal tissue may simply persist and progress no further or may even regress spontaneously; but in at least 30–40% of cases, progression will occur, giving rise, over a period of several years, to a frank invasive carcinoma (Figure 23-9D,H)—a malignant lesion where cells cross or destroy the basal lamina, invade the underlying tissue, and metastasize via the lymphatic vessels. Surgical cure becomes progressively more difficult as the invasive growth spreads.
As we have seen, cancers in general seem to arise by a process in which an initial population of slightly abnormal cells, descendants of a single mutant ancestor, evolves from bad to worse through successive cycles of mutation and natural selection. At each stage, one cell acquires an additional mutation that gives it a selective advantage over its neighbors, making it better able to thrive in its environment—an environment that, inside a tumor, may be harsh, with low levels of oxygen, scarce nutrients, and the natural barriers to growth presented by the surrounding normal tissues. The offspring of this well-adapted cell will continue to divide, eventually taking over the tumor and becoming the dominant clone in the developing lesion (Figure 23-11). Thus, tumors grow in fits and starts, as additional advantageous mutations arise and the cells bearing them flourish. Their evolution involves a large element of chance and usually takes many years; most of us die of other ailments before cancer has had time to develop.
Clonal evolution. A tumor develops through repeated rounds of mutation and proliferation, giving rise eventually to a clone of fully malignant cancer cells. At each step, a single cell undergoes a mutation that enhances cell proliferation, so that its (more...)
Why are so many mutations needed? One reason is that cellular processes are controlled in complex and interconnected ways; cells employ redundant regulatory mechanisms to help them maintain tight and precise control over their behavior. Thus, many different regulatory systems have to be disrupted before a cell can throw off its normal restraints and behave defiantly as a malignant cancer cell. In addition, tumor cells may meet new barriers to further expansion at each stage of the evolutionary process. For example, oxygen and nutrients do not become limiting until a tumor is one or two millimeters in diameter, at which point the cells in the tumor interior may not have adequate access to such necessary resources. Each new barrier, whether physical or physiological, must be overcome by the acquisition of additional mutations.
In general, the rate of evolution in any population would be expected to depend on four main parameters: (1) the mutation rate, that is, the probability per gene per unit time that any given member of the population will undergo genetic change; (2) the number of individuals in the population; (3) the rate of reproduction, that is, the average number of generations of progeny produced per unit time; and (4) the selective advantage enjoyed by successful mutant individuals, that is, the ratio of the number of surviving fertile progeny they produce per unit time to the number of surviving fertile progeny produced by nonmutant individuals. These are the critical factors for the evolution of cancer cells in a multicellular organism, just as they are for the evolution of organisms on the surface of the Earth.
Clearly the rate of progression toward cancer depends on many things beside the changing genotype of the individual cancer cell. Equally, it is plain that there are a number of quite disparate genetic properties that might help a cancer cell to be evolutionarily successful. In later sections, we shall examine the molecular changes that confer these properties. But first it is helpful to consider in general terms what the key properties actually are: what special capabilities are common to the majority of cancer cells and responsible for their bad behavior?
The great majority of human cancers show signs of a dramatically enhanced mutation rate: the cells are said to be genetically unstable. This instability can take various forms. Some cancer cells are defective in the ability to repair local DNA damage or to correct replication errors that affect individual nucleotides. These cells tend to accumulate more point mutations and small, localized DNA sequence changes than do normal cells. Other cancer cells have trouble maintaining the integrity of their chromosomes and thus display gross abnormalities in their karyotype (Figure 23-12). From an evolutionary perspective this is not a surprise: one might expect that genetic instability would promote the formation of cancer, as it increases the probability that cells will experience a mutation that will lead toward malignancy. In fact, it seems that some degree of genetic instability may be essential for the development of cancer; at the very least it appears to make a powerful contribution to cancer progression.
Chromosomes from a breast tumor displaying abnormalities in structure and number. Chromosomes were prepared from a breast tumor cell in metaphase, spread on a glass slide, and stained with (A) a general DNA stain or (B) a combination of fluorescent stains (more...)
Different tumors—even from the same tissues—can show different kinds of genetic instability, caused by mutations in one or another of a very specific set of genes whose products are needed to protect the genome from alteration. As mentioned earlier, people who inherit mutations in these genes are found to have a raised incidence of cancer. Although such cancer-prone conditions are relatively rare, they include examples of mutations in practically every type of gene known to be required for genetic stability, confirming that loss of this stability can have a causative role in cancer no matter how it occurs.
Most often, the destabilizing mutations are not inherited, but arise de novo as a tumor develops, helping the cancer cell to accumulate mutations much more rapidly than its neighbors do. It is important, however, to note that genetic instability does not, in itself, give a cell a selective advantage. On the contrary, genetic instability actually damages a cell's fitness, as most random mutations are harmful. Thus, a genetically unstable cell will not be favored by selection, unless it has additional properties or manages to accrue additional mutations that confer some competitive advantage. It seems that some “optimum” level of genetic instability exists for the development of cancer, making a cell mutable enough to evolve dangerously, but not so mutable that it dies (Figure 23-13).
Genetic instability and tumor progression. Cells that maintain an optimum level of genetic instability may be the most successful in the race to form a tumor. (A) In normal cells, the intrinsic amount of genetic instability is low. Thus when normal cells (more...)
Just as an increased mutation rate can raise the probability of cancer progression, so can any circumstance that increases the number of cells available for mutating. The bigger the clone of mutant cells resulting from an early mutation, the greater the chance that an additional mutation will allow the cancer to progress, until its growth is completely out of control and malignant. Thus, at every stage in the development of cancer, mutations that help cells to increase in number are critical.
How can a mutation have this effect? The most obvious way is to increase the rate of cell division. Indeed, mutations that tend to make cells blind to the normal restraints on cell division are a common feature of cancer, as we shall discuss in detail later. It has become increasingly clear, however, that such mutations are not the only—or necessarily the most important—mechanism for increasing cell number. In normal adult tissues, especially those at risk of cancer, cells may proliferate continually; but their numbers remain steady because cell production is balanced by cell loss. Programmed cell death by apoptosis very often has an essential role in this balance, as we saw in Chapters 17 and 22. If too many cells are generated, the rate of apoptosis increases to dispose of the surplus. One of the most important properties of cancer cells, therefore, is that they fail to commit suicide when a normal cell would honorably do so.
Mutations can also increase the size of a clone of mutant cells by altering their ability to differentiate, as illustrated by the situation in the uterine cervix, discussed earlier. Like the epidermis of the skin and many other epithelia, the epithelium of the uterine cervix normally renews itself continually by shedding terminally differentiated cells from its outer surface and generating replacements from stem cells in the basal layer. On average, each normal stem cell division generates one daughter stem cell and one cell that is condemned to terminal differentiation and a cessation of cell division. If the stem cell divides more rapidly, terminally differentiated cells will be produced and shed more rapidly, but a balance of genesis and destruction will still be maintained. Thus, for an abnormal stem cell to generate a steadily growing clone of mutant progeny, the basic rules must be upset: either more than 50% of the daughter cells must remain as stem cells or the process of differentiation must be deranged so that daughter cells that embark on this route somehow retain an ability to carry on dividing indefinitely and avoid dying or being discarded at the end of the production line (Figure 23-14).
Normal and deranged control of cell production from stem cells. (A) The normal strategy for producing new differentiated cells. (B and C) Two types of derangement that can give rise to the unbridled proliferation characteristic of cancer. Note that an (more...)
Presumably, the development of such properties underlies the progression from low-grade intraepithelial neoplasia of the uterine cervix to high-grade intraepithelial neoplasia and malignant cancer (see Figure 23-9). Similar considerations apply to the development of cancer in other tissues that rely on stem cells, such as the skin, the lining of the gut, and the hemopoietic system. Several forms of leukemia, for example, seem to arise from a disruption of the normal program of differentiation, such that a committed progenitor of a particular type of blood cell continues to divide indefinitely, instead of differentiating terminally in the normal way and dying after a strictly limited number of division cycles (as discussed in Chapter 22).
In conclusion, changes that block the normal maturation of cells toward a nondividing, terminally differentiated state or prevent normal programmed cell death play an essential part in many cancers.
Many normal cells cease to divide when they mature into terminally differentiated, specialized cells. Differentiation is not, however, the only condition that can arrest cell proliferation. Cells also cease to divide when they are stressed or when they detect damage to their DNA. Further, most normal human cells, when removed from a tissue and tested in culture for their ability to proliferate, appear to show a set limit on the number of times they can divide. Once cells progress through a certain number of population doublings—25 to 50 for human fibroblasts, for example—they simply stop proliferating, a process termed replicative cell senescence (discussed in Chapter 17). It is possible that, as a person ages, some cells may reach this limit to their proliferation— particularly in tissues requiring constant renewal, such as the epidermis or the lining of the gut. If a cell in such circumstances is to persist in dividing so as to generate a cancer, it must escape the restraints of replicative senescence. In fact, cancer cells, when tested in culture, often behave as “immortalized”: they continue dividing indefinitely, unlike their normal counterparts.
While these facts are well established, it is not yet clear precisely how they relate to the cancer disease process. Despite the findings in culture, there is remarkably little solid information about the importance of replicative senescence in normal tissues of intact human beings. According to one view, replicative senescence is a useful mechanism to protect us against cancer—an added barrier that cancer cells have to break through. According to another school of thought, cells in most tissues never actually reach replicative senescence in the course of a human lifetime, and the “immortality” of cancer cells is merely a side-effect of selection for some other property they need to have. Some recent studies, discussed later in the chapter, suggest a third view, radically different from both of the other two. The proposal is that many cells in normal tissues undergo replicative cell senescence and slow down or halt their proliferation as a person ages, and that this creates circumstances in which cancer cells can thrive all the better by continuing to divide at full throttle. On this view, replicative cell senescence, far from protecting us from the growth of tumors, creates a breeding ground for mutant cells that evade the normal controls and overrun the tissue because they face no competition from their senescent normal neighbors. The mutations that allow continued proliferation may confer at the same time other cancerous traits, such as genetic instability or a general disregard for cell-cycle controls, leading on to progressively more disordered behavior. In this way, replicative cell senescence in a self-renewing tissue might be expected to favor the genesis of cancer; it could be a part of the reason why cancer is predominantly a disease of old age.
Studies at a molecular level may soon clarify the picture. Later in the chapter, we see that replicative cell senescence in human cells is related to the shortening of telomeres—the repetitive DNA sequences and associated proteins that cap the ends of each chromosome. And we discuss how some cancers may arise from the dangerous ways in which certain mutations can allow cells to escape the block to cell division that normal cells encounter when their telomeres get too short.
Metastasis is the most feared—and least understood—aspect of cancer. By spreading throughout the body a cancer becomes almost impossible to eradicate surgically or by localized irradiation, and thus deadly. Metastasis is itself a multistep process: cells have to break away from the primary tumor, invade local tissues and vessels, and establish new cellular colonies at distant sites. Each of these events is, in itself, fairly complex and the molecular mechanisms involved are not yet clear.
For a cancer cell to metastasize, it must first detach from the parent tumor; key to this escape is an ability to invade neighboring tissues. Such invasiveness is the defining property of malignant tumors, which show a disorganized pattern of growth and ragged borders, with extensions into the surrounding tissue (see, for example, Figure 23-3). Although invasiveness is not thoroughly understood, it almost certainly requires a disruption of the adhesive mechanisms that normally keep cells tethered to their proper neighbors.
The next step in the process—escape from the neighborhood of the primary tumor and establishment of colonies in distant tissues—is a complex, slow, and inefficient operation; few cells in the primary tumor achieve it. To metastasize successfully, a cell must penetrate a blood vessel or a lymphatic vessel, cross the basal lamina and the endothelial lining of the vessel so as to enter the circulation, exit from the circulation elsewhere in the body, and survive and proliferate in the new environment in which it finds itself (Figure 23-15). Many cancers may invade local connective tissues but do not succeed in forming metastases before they are discovered and surgically removed. Only a tiny proportion of malignant cells manage to escape into the circulation; and experiments show that only a tiny proportion of these, less than one in thousands, perhaps one in millions, survive to form metastases. What seems to distinguish cells that are able to establish metastases is their ability to survive and grow after settling in an alien site.
Steps in the process of metastasis. This example illustrates the spread of a tumor from an organ such as the lung or bladder to the liver. Tumor cells may enter the bloodstream directly by crossing the wall of a blood vessel, as diagrammed here, or, more (more...)
It is thought that normal cells depend on molecular survival signals that are peculiar to their normal environment; when deprived of these signals, they activate their cell death machinery and undergo apoptosis. Cancer cells capable of metastasis are often relatively resistant to apoptosis compared with normal cells and therefore can survive and continue to grow after escaping from their proper home (Figure 23-16).
Colon cancer invading the smooth muscle layer that lies beneath the colon epithelium. In this tissue slice, colorectal cancer cells can be seen growing between the muscle fibers (pink). Some stages in the development of this type of cancer are shown in (more...)
In addition to all these requirements, to grow large, a tumor must recruit an adequate blood supply. Thus, angiogenesis, the formation of new blood vessels, is a necessity for growth of both primary tumors and metastases. Although normal tissues have an automatic mechanism to attract an increased blood supply when they require it (as discussed in Chapter 22), many tumors achieve rapid growth by switching on enhanced production of angiogenic signals. The new blood vessels supply the tumor with nutrients and oxygen, and they may also provide an easier escape route for metastatic cells.
Clearly, to be successful as a cancer a cell must acquire a whole range of aberrant properties—a collection of subversive new skills—as it evolves. Different cancers require different combinations of properties. Nevertheless, we can draw up a short list of the key behaviors of cancer cells in general:
They disregard the external and internal signals that regulate cell proliferation.
They tend to avoid suicide by apoptosis.
They circumvent programmed limitations to proliferation, escaping replicative senescence and avoiding differentiation.
They are genetically unstable.
They escape from their home tissues (that is, they are invasive).
They survive and proliferate in foreign sites (that is, they metastasize).
In the later sections of the chapter, we shall examine the mutations and molecular mechanisms that underlie these properties. But first, we must consider the external factors that can help to cause the disease.
Cancer cells, by definition, proliferate in defiance of normal controls (that is, they are neoplastic) and are able to invade and colonize surrounding tissues (that is, they are malignant). By giving rise to secondary tumors, or metastases, they become difficult to eradicate surgically. Most cancers are thought to originate from a single cell that has experienced an initial mutation, but the progeny of this cell must undergo further changes, requiring numerous additional mutations, to become cancerous. This phenomenon of tumor progression, which usually takes many years, reflects the unfortunate operation of evolution by mutation and natural selection among somatic cells.
The rational treatment of cancer requires an understanding of the special properties that cancer cells acquire as they evolve, multiply, and spread. These special properties include alterations in cell signaling pathways, enabling the cells in a tumor to ignore the signals from their environment that normally keep cell proliferation under tight control. In this way, the cells are first able to proliferate abnormally in their original tissue and then to metastasize, surviving and proliferating in foreign tissues. As part of the evolutionary process of tumor progression, cancer cells also acquire an abnormal aversion to suicide, and they avoid or break free of programmed limitations to proliferation—including replicative senescence and the normal pathways of differentiation that would otherwise hamper their ability to grow and divide.
Since many mutations are needed to confer this whole collection of bad properties, it is perhaps not surprising to find that nearly all cancer cells are observed to have the additional property of being abnormally mutable, having acquired one or more defects in various aspects of their DNA metabolism. This genetic instability speeds the cell's acquisition of the complex set of alterations that are required for neoplasia and malignancy.
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