Cancer, then, is a disease in which a single normal body cell undergoes a genetic transformation into a cancer cell. This cell and its descendants, proliferating across many years, produce the population of cells that we recognize as a tumor, and tumors produce the symptoms that an individual experiences as cancer.
Even this picture, although accurate in its essence, did not represent a complete description of the events involved in tumor formation. Additional research revealed that as a tumor develops, the cells of which it is composed become different from one another as they acquire new traits and form distinct subpopulations of cells within the tumor. As shown in Figure 5, these changes allow the cells that experience them to compete with increasing success against cells that lack the full set of changes. The development of cancer, then, occurs as a result of a series of clonal expansions from a single ancestral cell.
A second critical understanding that emerged from studying the biology of cancer cells is that these cells show a wide range of important differences from normal cells. For example, cancer cells are genetically unstable and prone to rearrangements, duplications, and deletions of their chromosomes that cause their progeny to display unusual traits. Thus, although a tumor as a whole is monoclonal in origin, it may contain a large number of cells with diverse characteristics.
Cancerous cells also look and act differently from normal cells. In most normal cells, the nucleus is only about one-fifth the size of the cell; in cancerous cells, the nucleus may occupy most of the cell's volume. Tumor cells also often lack the differentiated traits of the normal cell from which they arose. Whereas normal secretory cells produce and release mucus, cancers derived from these cells may have lost this characteristic. Likewise, epithelial cells usually contain large amounts of keratin, but the cells that make up skin cancer may no longer accumulate this protein in their cytoplasms.
The key difference between normal and cancerous cells, however, is that cancer cells have lost the restraints on growth that characterize normal cells. Significantly, a large number of cells in a tumor are engaged in mitosis, whereas mitosis is a relatively rare event in most normal tissues. Cancer cells also demonstrate a variety of unusual characteristics when grown in culture; two such examples are a lack of contact inhibition and a reduced dependence on the presence of growth factors in the environment. In contrast to normal cells, cancer cells do not cooperate with other cells in their environment. They often proliferate indefinitely in tissue culture. The ability to divide for an apparently unlimited number of generations is another important characteristic of the cancerous state, allowing a tumor composed of such cells to grow without the constraints that normally limit cell growth.
Figure 5 - A series of changes leads to tumor formation. Tumor formation occurs as a result of successive clonal expansions. This figure illustrates only three such changes; the development of many cancers likely involves more than three. D
A unified view. By the mid-1970s, scientists had started to develop the basis of our modern molecular understanding of cancer. In particular, the relationship Ames and others had established between mutagenicity and carcinogenicity provided substantial support for the idea that chemical carcinogens act directly through their ability to damage cellular genes. This idea led to a straightforward model for the initiation of cancer: Carcinogens induce mutations in critical genes, and these mutations direct the cell in which they occur, as well as all of its progeny cells, to grow abnormally. The result of this abnormal growth appears years later as a tumor. The model could even explain the observation that cancer sometimes appears to run in families: If cancer is caused by mutations in critical genes, then people who inherit such mutations would be more susceptible to cancer's development than people who do not.
As exciting as it was to see a unified view of cancer begin to emerge from the earlier confusion, cancer researchers knew their work was not finished. The primary flaw in their emerging explanation was that the nature of these cancer-causing mutations was unknown. Indeed, their very existence had yet to be proven. Evidence from work with cancer-causing viruses suggested that only a small number of genes were involved, and evidence from cell biology pointed to genes that normally control cell division. But now scientists asked new questions: Exactly which genes are involved? What are their specific roles in the cell? and How do their functions change as a result of mutation?
It would take another 20 years and a revolution in the techniques of biological research to answer these questions. However, today our picture of the causes and development of cancer is so detailed that scientists find themselves in the extraordinary position of not only knowing many of the genes involved but also being able to target prevention, detection, and treatment efforts directly at these genes.
A central feature of today's molecular view of cancer is that cancer does not develop all at once, but across time, as a long and complex succession of genetic changes. Each change enables precancerous cells to acquire some of the traits that together create the malignant growth of cancer cells.
Two categories of genes play major roles in triggering cancer. In their normal forms, these genes control the cell cycle, the sequence of events by which cells enlarge and divide. One category of genes, called proto-oncogenes, encourages cell division. The other category, called tumor-suppressor genes, inhibits it. Together, proto-oncogenes and tumor-suppressor genes coordinate the regulated growth that normally ensures that each tissue and organ in the body maintains a size and structure that meets the body's needs.
What happens when proto-oncogenes or tumor-suppressor genes are mutated? Mutated proto-oncogenes become oncogenes, genes that stimulate excessive division. And mutations in tumor-suppressor genes inactivate these genes, eliminating the critical inhibition of cell division that normally prevents excessive growth. Collectively, mutations in these two categories of genes account for much of the uncontrolled cell division that occurs in human cancers (Figure 6).
The role of oncogenes. How do proto-oncogenes, or, more accurately, the oncogenes they become after mutation, contribute to the development of cancer? Most proto-oncogenes code for proteins that are involved in molecular pathways that receive and process growth-stimulating signals from other cells in a tissue. Typically, such signaling begins with the production of a growth factor, a protein that stimulates division. Growth factors move through the spaces between cells and attach to specific receptor proteins located on the surfaces of neighboring cells. When a growth-stimulating factor binds to such a receptor, the receptor conveys a stimulatory signal to proteins in the cytoplasm. These proteins emit stimulatory signals to other proteins in the cell until the division-promoting message reaches the cell's nucleus and activates a set of genes that help move the cell through its growth cycle.
|PDGF||codes for a protein called platelet-derived growth factor (involved in some forms of brain cancer)|
|Ki-ras||codes for a protein involved in a stimulatory signaling pathway (involved in lung, ovarian, colon, and pancreatic cancer)|
|MDM2||codes for a protein that is an antagonist of the p53 tumor-suppressor protein (involved in certain connective tissue cancers)|
|NF-1||codes for a protein that inhibits a stimulatory protein (involved in myeloid leukemia)|
|RB||codes for the pRB protein, a key inhibitor of the cell cycle (involved in retinoblastoma and bone, bladder, and breast cancer)|
|BRCA1||codes for a protein whose function is still unknown (involved in breast and ovarian cancers)|
Oncogenes, the mutated forms of these proto-oncogenes, cause the proteins involved in these growth-promoting pathways to be overactive. Thus, the cell proliferates much faster than it would if the mutation had not occurred. Some oncogenes cause cells to overproduce growth factors. These factors stimulate the growth of neighboring cells, but they also may drive excessive division of the cells that just produced them. Other oncogenes produce aberrant receptor proteins that release stimulatory signals into the cytoplasm even when no growth factors are present in the environment. Still other oncogenes disrupt parts of the signal cascade that occurs in a cell's cytoplasm such that the cell's nucleus receives stimulatory messages continuously, even when growth factor receptors are not prompting them.
The role of tumor-suppressor genes. To become cancerous, cells also must break free from the inhibitory messages that normally counterbalance these growth-stimulating pathways. In normal cells, inhibitory messages flow to a cell's nucleus much like stimulatory messages do. But when this flow is interrupted, the cell can ignore the normally powerful inhibitory messages at its surface.
Scientists are still trying to identify the normal functions of many known tumor-suppressor genes. Some of these genes apparently code for proteins that operate as parts of specific inhibitory pathways. When a mutation causes such proteins to be inactivate or absent, these inhibitory pathways no longer function normally. Other tumor-suppressor genes appear to block the flow of signals through growth-stimulating pathways; when these genes no longer function properly, such growth-promoting pathways may operate without normal restraint. Mutations in all tumor-suppressor genes, however, apparently inactivate critical tumor-suppressor proteins, depriving cells of this restraint on cell division.
The body's back-up systems. In addition to the controls on proliferation afforded by the coordinated action of proto-oncogenes and tumor suppressor genes, cells also have at least three other systems that can help them avoid runaway cell division. The first of these systems is the DNA repair system. This system operates in virtually every cell in the body, detecting and correcting errors in DNA. Across a lifetime, a person's genes are under constant attack, both by carcinogens imported from the environment and by chemicals produced in the cell itself. Errors also occur during DNA replication. In most cases, such errors are rapidly corrected by the cell's DNA repair system. Should the system fail, however, the error (now a mutation) becomes a permanent feature in that cell and in all of its descendants.
The system's normally high efficiency is one reason why many years typically must pass before all the mutations required for cancer to develop occur together in one cell. Mutations in DNA repair genes themselves, however, can undermine this repair system in a particularly devastating way: They damage a cell's ability to repair errors in its DNA. As a result, mutations appear in the cell (including mutations in genes that control cell growth) much more frequently than normal.
A second cellular back-up system prompts a cell to commit suicide (undergo apoptosis) if some essential component is damaged or its control system is deregulated. This observation suggests that tumors arise from cells that have managed to evade such death. One way of avoiding apoptosis involves the p53 protein. In its normal form, this protein not only halts cell division, but induces apoptosis in abnormal cells. The product of a tumor-suppressor gene, p53 is inactivated in many types of cancers.
This ability to avoid apoptosis endangers cancer patients in two ways. First, it contributes to the growth of tumors. Second, it makes cancer cells resistant to treatment. Scientists used to think that radiation and chemotherapeutic drugs killed cancer cells directly by harming their DNA. It seems clear now that such therapy only slightly damages the DNA in cells; the damaged cells, in response, actively kill themselves. This discovery suggests that cancer cells able to evade apoptosis will be less responsive to treatment than other cells.
A third back-up system limits the number of times a cell can divide, and so ensures that cells cannot reproduce endlessly. This system is governed by a counting mechanism that involves the DNA segments at the ends of chromosomes. Called telomeres, these segments shorten each time a chromosome replicates. Once the telomeres are shorter than some threshold length, they trigger an internal signal that causes the cell to stop dividing. If the cells continue dividing, further shortening of the telomeres eventually causes the chromosomes to break apart or fuse with one another, a genetic crisis that is inevitably fatal to the cell.
Early observations of cancer cells grown in culture revealed that, unlike normal cells, cancer cells can proliferate indefinitely. Scientists have recently discovered the molecular basis for this characteristic—an enzyme called telomerase, that systematically replaces telomeric segments that are trimmed away during each round of cell division. Telomerase is virtually absent from most mature cells, but is present in most cancer cells, where its action enables the cells to proliferate endlessly.
The multistep development of cancer. Cancer, then, does not develop all at once as a massive shift in cellular functions that results from a mutation in one or two wayward genes. Instead, it develops step-by-step, across time, as an accumulation of many molecular changes, each contributing some of the characteristics that eventually produce the malignant state. The number of cell divisions that occur during this process can be astronomically large—human tumors often become apparent only after they have grown to a size of 10 billion to 100 billion cells. As you might expect, the time frame involved also is very long— it normally takes decades to accumulate enough mutations to reach a malignant state.
Understanding cancer as a multistep process that occurs across long periods of time explains a number of long-standing observations. A key observation is the increase in incidence with age. Cancer is, for the most part, a disease of people who have lived long enough to have experienced a complex and extended succession of events. Because each change is a rare accident requiring years to occur, the whole process takes a very long time, and most of us die from other causes before it is complete.
Understanding cancer in this way also explains the increase in cancer incidence in people who experience unusual exposure to carcinogens, as well as the increased cancer risk of people who inherit predisposing mutations. Exposure to carcinogens increases the likelihood that certain harmful changes will occur, greatly increasing the probability of developing cancer during a normal life span. Similarly, inheriting a cancer-susceptibility mutation means that instead of that mutation being a rare event, it already has occurred, and not just in one or two cells, but in all the body's cells. In other words, the process of tumor formation has leapfrogged over one of its early steps. Now the accumulation of changes required to reach the malignant state, which usually requires several decades to occur, may take place in one or two.
Finally, understanding the development of cancer as a multistep process also explains the lag time that often separates exposure to a cancer-causing agent and the development of cancer. This explains, for example, the observation that severe sunburns in children can lead to the development of skin cancer decades later. It also explains the 20-to-25-year lag between the onset of widespread cigarette smoking among women after World War II and the massive increase in lung cancer that occurred among women in the 1970s.
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