chapter 18
If a cancer is detected, chances are it has been present for years, perhaps decades.
A cancer takes time to grow because it is the culmination of a series of genetic and genomic changes—mutations—that enable certain cells to divide more frequently than normal, forming a new growth that enlarges, eventually crowding healthy tissue.
A single gene that causes a variety of cancers when mutant is p53. Recall from chapter 12 that the p53 protein transcription factor "decides" whether a cell repairs DNA replication errors or dies by apoptosis. If a cell loses a p53 gene, or if the gene mutates and malfunctions, a cell with damaged DNA is permit- ted to divide, and cancer may be the result. More than half of human cancers arise from a point mutation or deletion in the p53 gene. This may be because p53 protein is a genetic mediator between environmental insults and development of cancer.
A type of skin cancer, for example, is caused by a p53 mutation in skin cells damaged by an excessive inflammatory response that can result from repeated sunburns. That is, p53 may be the link between sun exposure and skin cancer. In most p53-related cancers, mutations occur only in somatic cells. However, in the germline condition Li-Fraumeni syndrome, family members who inherit a mutation in the p53 gene have a very high risk of developing cancer—50 percent do so by age 30, and 90 percent by age 70. A somatic p53 mutation in the affected tissue results in cancer because a germline mutation in the gene is already present.
Cancer cells can divide continuously if given sufficient nutrients and space.
Cells vary greatly in their capacity to divide. Cancer cells divide more frequently or more times than the cells from which they arise. Yet even the fastest-dividing cancer cells, which complete mitosis every 18 to 24 hours, do not divide as often as some cells in a normal human embryo do. A tumor grows more slowly at first because fewer cells divide. By the time the tumor is the size of a pea—when it is usually detectable—billions of cells are actively dividing. A cancerous tumor eventually grows faster than surrounding tissue because a greater proportion of its cells is dividing.
The effect of driver mutations is cumulative. The ini- tial mutation is called a "gatekeeper," and it enables a normal epithelial (lining cell) to divide slightly faster than others. A clone of faster-dividing cells gradually accumulates. Then a second mutation boosts the division rate in the already mutation-bearing cells, and their proportion within the tissue increases.
Even if each driver boosts division rate by only 0.4 percent, and if cells divide only once or twice a week, in several years the tumor that a person might be able to feel will already consist of billions of cells. Additional mutations drive invasiveness and metastasis. Some mutations that enable a tumor to metastasize may actually have been present from the very beginning of the disease, almost as if they are waiting to spring into action.
Cell fate refers to differentiation (specialization). Cell survival refers to oxygen availability and preventing apoptosis.
Genome maintenance refers to the abilities to survive in the presence of reactive oxygen species and toxins, to repair DNA, to maintain chromosome integrity and structure, and to correctly splice mRNA molecules.
Cancer is a complication of being a many-celled organism. Our specialized cells must follow a schedule of mitosis—the cell cycle—so that organs and other body parts grow appropriately during childhood, stay a particular size and shape throughout adulthood, and repair damage by replacing tissue.
If a cell in solid tissue escapes normal controls on its division rate, it forms a growth called a tumor. In the blood, a "liquid tumor" divides more frequently than others, taking over the population of blood cells.
Most mutations that cause cancer are in oncogenes or tumor suppressor genes. The effects of mutations in oncogenes are typically dominant, and those of tumor suppressor genes recessive. A 3rd category of cancer genes include mismatch mutations in DNA repair genes that allow other mutations to persist. When these other mutations activate oncogenes or inactivate tumor suppressor genes, cancer result.
Most DNA repair disorders are inherited in a single-gene fashion, and are quite rare. They typically cause diverse and widespread tumors, often beginning at a young age.
Genes that normally trigger cell division are called proto-oncogenes. They are active where and when high rates of cell division are necessary, such as in a wound or in an embryo. When proto-oncogenes are transcribed and trans- lated too rapidly or frequently, or perhaps at the wrong time in development or place in the body, they function as oncogenes. Usually oncogene activation is asso- ciated with a point mutation or a chromosomal translocation or inversion that places the gene next to another that is more highly expressed (transcribed). Oncogene activation causes a gain-of-function. In contrast, a tumor suppressor gene mutation is usually a deletion that causes a loss-of-function
Proto-oncogenes can also become oncogenes by being physically next to highly transcribed genes. Three examples of genes that can activate proto-oncogenes are a viral gene, a gene encoding a hormone, and parts of antibody genes.
Another way that an oncogene can cause cancer is by excessive response to a growth factor. In about 25 percent of women with breast cancer, affected cells have 1 to 2 million copies of a cell surface protein called HER2 that is the product of an oncogene. The normal number of these proteins is only 20,000 to 100,000.
The HER2 proteins are receptors for epidermal growth factor. In breast cells, the receptors traverse the plasma membrane, extending outside the cell into the extracellular matrix and also dipping into the cytoplasm. They function as a tyrosine kinase. When the growth factor binds to the tyrosine (an amino acid) of the receptor, the tyrosine picks up a phosphate group, which signals the cell to activate transcription of genes that stimulate cell division. In HER2 breast cancer, too many tyrosine kinase receptors send too many signals to divide. HER2 breast cancer usually strikes early in adulthood and spreads quickly. However, a monoclonal antibody-based drug called trastuzumab (Herceptin) binds to the receptors, blocking the signal to divide. Interestingly, Herceptin works when the extra receptors arise from multiple copies of the gene, rather than from extra transcription of a single HER2 gene.
The most fundamental characteristic of cancer is the underlying disruption of the cell cycle. Cancer begins when a cell divides more frequently, or more times, than the noncancerous cell it descended from. Mitosis in a cancer cell is like a runaway train, racing along without signals and control points.
The timing, rate, and number of mitoses a cell undergoes depend on protein growth factors and signaling molecules from outside the cell, and on transcription factors from within. Because these biochemicals are under genetic control, so is the cell cycle. Cancer cells arise often, because mitoses are so frequent that an occasional cell escapes control. However,immune system destroys most cancer cells after recognizing tumor-specific antigens on their surfaces.
Cancer is genetic, because it is caused by changes in DNA, but not usually inherited. Only about 10 percent of cases result from inheriting a cancer susceptibility allele from a parent. The inherited allele is a germline mutation, mean- ing that it is present in every cell of the individual, including the gametes. Cancer develops when a second mutation occurs in the other allele in a somatic cell in the affected body part
the majority of cancers are sporadic, and caused by somatic mutations that affect only nonsex cells. A sporadic cancer may result from a single dominant mutation or from two recessive mutations in copies of the same gene. The cell loses control of its cell cycle and accelerated division of its daughter cells forms the tumor. Eventually, tumor cells may contain dozens of mutations that are not in neighboring, healthy cells.
An oncogene is a gene that causes cancer when inap-propriately activated.
tumor suppressor genes, which cause cancer when they are deleted or inactivated. The normal function of a tumor suppressor gene is to keep the cell cycle running at the appropriate rate for a particular cell type under particular conditions.
A virus infecting a cell may insert DNA next to a proto-oncogene. When the viral DNA is rapidly transcribed, the adjacent proto-oncogene (now an oncogene) is also rapidly transcribed. Increased production of the oncogene's encoded protein then switches on genes that promote mitosis, triggering the cascade of changes that leads to cancer. Viral damage to a human genome may be what one researcher calls "catastrophic," activating and amplifying oncogenes as well as inverting and translocating chromosomes. Viruses cause cervical cancer, Kaposi sarcoma, and acute T cell leukemia.
A proto-oncogene may be activated when it is moved next to a gene that is normally very actively transcribed. This happens when an inversion on chromosome 11 places a proto- oncogene next to a DNA sequence that controls transcription of the parathyroid hormone gene. When the gland synthesizes the hormone, the oncogene is expressed, too. Cells in the gland divide, forming a tumor.
Antibody genes are among the most highly transcribed, so it isn't surprising that a translocation or inversion that places a proto-oncogene next to an antibody gene causes cancer.
A proto-oncogene may not only move next to another gene, but also be transcribed and translated with it as if they are one gene. The double gene product, called a fusion protein, activates or lifts control of cell division. For example, in acute promyelocytic leukemia, a translocation between chromosomes 15 and 17 brings together a gene coding for the retinoic acid cell surface receptor and an oncogene called myl. The fusion protein functions as a transcription factor, which, when overexpressed, causes cancer. The nature of this fusion protein explains why some patients who receive retinoid (vitamin A-based) drugs recover. Their immature, dedifferentiated cancer cells, apparently stuck in an early stage of development where they divide frequently, suddenly differentiate, mature, and die. Perhaps the cancer- causing fusion protein prevents affected white blood cells from getting enough retinoids to specialize, locking them in an embryonic-like, rapidly dividing state. Supplying extra retinoids allows the cells to resume their normal developmental pathway.
The following sections look at specific oncogenes and tumor suppressor genes. Chromosome abnormalities can cause these mutations. The chromosomes in cancer cells may be abnormal in number and/or structure. They may bear translocations, inversions, or have pieces missing or extra.
A translocation that joins parts of nonhomologous chromosomes can hike expression of a gene enough to turn it into an oncogene. A duplication can increase the number of copies of a particular oncogene from two—one on each of a pair of homologs—to up to 100. A deletion may remove a tumor suppressor gene. A one-time event called chromothripsis shatters several chromosomes and may kill the cell—or trigger cancer.
Cancer may also begin when cells lose some of their distinguishing characteristics as mutations occur when they divide. Or, cells on the road to cancer may begin to express "stemness" genes that override signals to remain specialized
Another possible origin of cancer may be a loss of balance at the tissue level in favor of cells that can divide continually or frequently—like a population growing faster if more of its members are of reproductive age. Consider a tissue that is 5 percent stem cells, 10 percent progenitors, and 85 percent differentiated cells. If a mutation, over time, shifts the balance in a way that creates more stem and progenitor cells, the extra cells pile up, and a tumor forms.
Researchers use several techniques that compare tumors to deduce the mutational steps that drive the dis- ease. One approach is to count and compare mutations in tumor cells from people at different stages of the same type of cancer. The older the tumor, the more genetic changes have accumulated. A mutation present in all stages among several individuals' tumors acts early in the disease process, whereas a mutation seen only in the tumor cells of sicker people acts later.
Another way to identify driver mutations that intervene after the gatekeeper is to study the cancer cells of patients who respond to a drug and then relapse. For example, an experimental drug that helped several patients with metastatic melanoma stopped working after 7 months for some patients, whose skin tumors came back. Their cancer cells had mutations in three genes other than the gatekeeper. These new mutations altered cancer cell surfaces and metabolism in ways that enabled the cells to ignore the drug and keep dividing and spreading. The changeability of a cancer is why a "cocktail" of drugs that act on different cellular pathways (such as cell adhesion or signal transduction) may be the best treatment approach, as it is for HIV infection.
A cancer cell is dedifferentiated, which means that it is less specialized than the normal cell types near it that it might have descended from. A skin cancer cell, for example, is rounder and softer than the flattened, scaly, healthy skin cells above it in the epidermis, and is more like a stem cell in both appearance and division rate. Cancer cell growth is unusual. Normal cells in a container divide to form a single layer; cancer cells pile up on one another. In an organism, this pileup would produce a tumor. Cancer cells that grow all over one another are said to lack contact inhibition—they do not stop dividing when they crowd other cells.
Cancer cells have surface structures that enable them to squeeze into any space, a property called invasiveness. They anchor themselves to tissue boundaries, called basement membranes, where they secrete enzymes that cut paths through healthy tissue. Unlike a benign tumor, an invasive malignant tumor grows irregularly, sending tentacles in all directions. The cell can move. Mutations affect the cytoskeleton, breaking down actin microfilaments and releasing actin molecules that migrate to the cell surface, mov- ing the cell from where it is anchored in surrounding tissue.
Cancer can begin at a cellular level in at least four ways: 1) activation of stem cells that produce cancer cells; 2) dedifferentiation; 3)increase in the proportion of a tissue that consists of stem or progenitor cells; and 4) faulty tissue repair.
Dedifferentiation is not an all-or-none phenomenon. Most cancer cells are more specialized than stem cells, but considerably less specialized than the differentiated cells near them in a tissue. From which does the cancer cell arise, the stem cell or the specialized cell? A cancer cell may descend from a stem cell that yields slightly differentiated daughter cells that retain the capacity to self-renew, or a cancer cell may arise from a specialized cell that loses some of its features and can divide. Certain stem cells, called cancer stem cells, veer from normal development and produce both cancer cells and abnormal specialized cells. Cancer stem cells are found in cancers of the brain, blood, and epithelium (particularly in the breast, colon, and prostate).
In cancer genetics, a driver mutation provides the selective growth advantage to a cell that defines the cancerous state. A passenger mutation occurs in a cancer cell, but does not cause or propel the cancer's growth or spread.
Drivers can be oncogenes or tumor suppressor genes, and may be generated from abnormal chromosomes.
Gametes keep their telomeres long using an enzyme, telomerase, that consists of RNA and protein. Part of the RNA—AAUCCC—is a template for the 6-DNA-base repeat TTAGGG that builds telomeres. Telomerase moves down the DNA like a zipper, adding six "teeth" (bases) at a time. Mutation in the gene that encodes telomerase, called TERT, causes some cancers.
In normal, specialized cells, telomerase is turned off and telomeres shrink, signaling a halt to cell division when they reach a certain size. In cancer cells, telomerase is turned back on. Telomeres extend, and this releases the normal brake on rapid cell division. As daughter cells of the original abnormal cell continue to divide uncontrollably, a tumor forms, grows, and may spread. Usually the longer the telomeres in cancer cells, the more advanced the disease. However, turning on telomerase production in a cell is not sufficient in itself to cause cancer.
A tumor is benign if it grows in place but does not spread into, or "invade," surrounding tissue. A tumor is cancerous, or malignant, if it infiltrates nearby tissue. Pieces of a malignant tumor can enter the bloodstream or lymphatic vessels and travel to other areas, where the cancer cells "seed" the formation of new tumors. The process of spreading is termed metastasis, which means "not standing still."
It is metastasis that makes a cancer deadly, because the new growth may be in an inaccessible part of the body, or genetically distinct enough from the original, or primary, tumor that drugs that were effective early in the illness no longer work. Metastases are difficult to detect. If a few sites of metastases appear on a medical scan, there may actually be dozens of the growths in the body.
Environmental factors contribute to cancer by mutating or altering the expression of genes that control the cell cycle, apoptosis, and DNA repair. Inheriting a susceptibility gene places a person farther along a particular road to cancer, but cancer can happen in somatic cells in anyone. It is more practical, for now, to identify environmental cancer triggers and develop ways to control them or limit our exposure to them, than to alter genes.
Looking at cancer at a population level reveals the interactions of genes and the environment. For example, researchers examined samples of non-Hodgkin's lymphoma tumors from 172 farmers, 65 of whom had a specific chromosomal trans- location. The 65 farmers were much more likely to have been exposed for long times to toxic insecticides, herbicides, fungicides, and fumigants, compared to the farmers with lymphoma who did not have the translocation. Determining precisely how an environmental factor such as diet affects cancer risk can be complicated. Consider the cruciferous vegetables, such as broccoli and brussels sprouts, which are associated with decreased risk of developing colon cancer. These vegetables release compounds called glucosinolates, which in turn activate "xenobiotic metabolizing enzymes" that detoxify carcinogenic products of cooked meat called heterocyclic aromatic amines. With a vegetable-poor, meaty diet, these amines accumulate. They cross the lining of the digestive tract and circulate to the liver, where enzymes metabolize them into compounds that cause driver mutations for colon cancer
A mutation in a gene that normally halts or slows the cell cycle can lift the constraint, leading to inappropriate mitosis. Failure to pause long enough to repair DNA can allow a mutation in an oncogene or tumor suppressor gene to persist.
Loss of control over telomere length may also contribute to cancer by affecting the cell cycle. Recall that telomeres, or chromosome tips, protect chromosomes from breaking. Human telomeres consist of the DNA sequence TTAGGG repeated thousands of times. The repeats are normally lost from the telomere ends as a cell matures, from 15 to 40 nucleotides per cell division. The more specialized a cell, the shorter its telomeres. The chromosomes in skin, nerve, and muscle cells, for example, have short telomeres. Chromosomes in a sperm cell or oocyte, however, have long telomeres. This makes sense—as the precursors of a new organism, gametes must retain the capacity to divide many times.
All of these changes that craft a cancer cell from a healthy cell, and the proliferation of cancer cells and eventual invasion and metastasis, take time. Cancer cells on the move eventually reach the bloodstream or lymphatic vessels, which take them to other body parts. This is metastasis.
Once a tumor has grown to the size of a pinhead, interior cancer cells respond to the oxygen-poor environment by secret- ing a protein, called vascular endothelial growth factor (VEGF). It stimulates nearby capillaries (the tiniest blood vessels) to sprout new branches that extend toward the tumor, bringing in oxygen and nutrients and removing wastes. This growth of new capillary extensions is called angiogenesis, and it is critical to a cancer's growth and spread. Capillaries may snake into and out of the tumor. Cancer cells wrap around the blood vessels and creep out upon this scaffolding, invading nearby tissue. In addi- tion to attracting their own blood supply, cancer cells may also secrete hormones that encourage their own growth. This is a new ability because the cells they descend from do not produce these hormones. When cancer cells move to a new body part, the DNA of secondary tumor cells often mutates, and chromosomes may break or rearrange. Many cancer cells are aneuploid (with missing or extra chromosomes). The metastasized cancer thus becomes a new genetic entity that may resist treatments that were effective against most cells of the original tumor.
Sequences of mutations in somatic cells, shattering of chromosomes, and changes in gene expression underlie the progression of cancer as it spreads. Mutations may affect the expression of other genes, but so may epigenetic influences, such as DNA methylation and chromatin remodeling.
One researcher calls the accumulating DNA changes that lie behind cancer "genomic scars."
Retinoblastoma is a rare childhood eye tumor. They have one germline mutant allele for the RB1 gene in each of their cells, and then cancer develops in a somatic cell where the second copy of the RB1 gene mutates. Therefore, inherited retinoblastoma requires two point mutations or deletions, one germline and one somatic. In some sporadic (noninherited) cases, two somatic mutations occur in the RB1 gene, one on each copy of chromosome 13. Either way, the can- cer usually starts in a cone cell of the retina, which pro- vides color vision. Study of retinoblastoma inspired the "two-hit" hypothesis of cancer causation—that two mutations (germline and somatic or two somatic) are required to cause a cancer related to tumor suppressor deletion or malfunction.
The discovery that many children with RB have deletions in the same region of the long arm of chromosome 13 led researchers to the RB1 gene and its protein product, which linked the cancer to control of the cell cycle. The RB1 protein normally binds transcription factors so that they cannot activate genes that carry out mitosis. It normally halts the cell cycle at G1. When the RB1 gene is mutant or missing, the hold on the transcription factor is released, and cell division ensues. For many years, the only treatment for retinoblastoma was removal of the affected eye. Today, children with an affected parent or sibling, who have a 50 percent chance of having inherited the mutant RB1 gene, can be monitored from birth so that noninvasive treatment (chemotherapy) can begin early. Full recovery is common. Mutations in the RB1 gene cause other cancers. Some children successfully treated for retinoblastoma develop bone cancer as teens or bladder cancer as adults. Mutant RB1 genes have been found in the cells of patients with breast, lung, or prostate cancers, or acute myeloid leukemia, who never had the eye tumors. Expression of the same genetic defect in different tissues may cause these cancers.
Only about 130 genes may have driver mutations, but genes that can yield passenger mutations, which occur in cancerous as well as noncancerous cells, are much more common. More than 99 percent of the mutations in cancer cells are passengers, just along for the ride.
Tumors vary greatly in the numbers of each type of mutation. A cancer generally has from two to eight driver mutations. The number of passenger mutations increases with age. For a 40-year-old and an 80-year-old with the same type of cancer, the older person's tumor cells will have many more passenger mutations than the younger person's tumor cells. This makes sense. The passage of time brings replication errors and environmental exposures.
A cancer cell looks different from a normal cell. Some cancer cells are rounder than the cells they descend from because they do not adhere to surrounding normal cells as strongly as other cells do. Because the plasma membrane is more fluid, different substances cross it. A cancer cell's surface may sport different antigens than are on other cells or different numbers of antigens that are also on normal cells. The "prostate specific antigen" (PSA) blood test that indicates increased risk of prostate can- cer, for example, detects elevated levels of this protein that may come from cancer cell surfaces.
When a cancer cell divides, both daughter cells are cancerous, because they inherit the altered cell cycle control. Therefore, cancer is said to be heritable because it is passed from parent cell to daughter cell. A cancer is also transplant- able. If a cancer cell is injected into a healthy animal of the same species, it will proliferate there.
Germline cancers are rare, but they have high penetrance and tend to strike earlier in life than sporadic cancers. Germline mutations may explain why some heavy smokers develop lung cancer, but many do not; the unlucky ones may have inherited a susceptibility allele.
Years of exposure to the carcinogens in smoke eventually cause a mutation in a tumor suppressor gene or oncogene of a lung cell, giving it a proliferative advantage. Without the susceptibility gene, two such somatic mutations are necessary to trigger the cancer. This, too, can be the result of an environmental insult, but it takes longer for two events to occur than one.
