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Cell_Biology_Alberts. Figure 20–39 Age-adjusted cancer death rates, United States, 1930–2008. Selected death rates, adjusted to the age distribution of the US population, are plotted for (A) females and (B) males. Note the dramatic rise in lung cancer for both sexes, following the pattern of tobacco smoking, and the fall in deaths from stomach cancer, thought to be related to a fall in rates of infection with Helicobacter pylori. Recent reductions in deaths per 100,000 populationdeaths per 100,000 population0 20 40 60 80 0 20 40 60 80stomach breast lung and bronchus uterus ovary pancreas stomach prostate lung and bronchus leukemia liver pancreas treatment. Age-adjusted data like these are needed to compensate for the inevitable increase in cancer as people live longer, on average. (Adapted from Cancer Facts and Figures, 2012. Data from U.S. Mortality Volumes 1930 to 1959, U.S. Mortality Data 1960 to 2008, National Center for health Statistics, Centers for Disease Control and


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Cell_Biology_Alberts. Prevention. © 2012, American Cancer (A) (B) Society, Inc., Surveillance Research.) with hepatitis-C virus, which has infected 170 million people worldwide, is also clearly associated with the development of liver cancer.


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Cell_Biology_Alberts. The main culprits, as shown in Table 20–2, are the DNA viruses. The DNA tumor viruses cause cancer by the most direct route—by interfering with controls of the cell cycle and apoptosis. To understand this type of viral carcinogenesis, it is important to review the life history of viruses. Many DNA viruses use the host cell’s DNA replication machinery to replicate their own genomes. However, to produce a large number of infectious virus particles within a single host cell, the DNA virus has to commandeer this machinery and drive it hard, breaking through the normal constraints on DNA replication and usually killing the host cell in the process. Many DNA viruses reproduce only in this way. But some have a second option: they can propagate their genome as a quiet, well-behaved passenger in the host cell, replicating in parallel with the host cell’s DNA (either integrated into the host genome, or as an extrachromosomal plasmid) in the course of ordinary cell-division cycles. These viruses


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Cell_Biology_Alberts. host cell, replicating in parallel with the host cell’s DNA (either integrated into the host genome, or as an extrachromosomal plasmid) in the course of ordinary cell-division cycles. These viruses will switch between two modes of existence according to circumstances, remaining latent and harmless for a long time, but then proliferating in occasional cells in a process that kills the host cell and generates large numbers of infectious particles.


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Cell_Biology_Alberts. Neither of these conditions converts the host cell to a cancerous character, nor is it in the interest of the virus to do so. But for viruses with a latent phase, accidents can occur that prematurely activate some of the viral proteins that the virus would normally use in its replicative phase to allow the viral DNA to replicate independently of the cell cycle. As described in the example below, this type of accident can switch on the persistent proliferation of the host cell itself, leading to cancer. Cancers of the Uterine Cervix Can Be Prevented by Vaccination Against human Papillomavirus


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Cell_Biology_Alberts. The papillomaviruses are a prime example of DNA tumor viruses. They are responsible for human warts and are especially important as a cause of carcinoma of the uterine cervix: this is the second commonest cancer of women in the world as a whole, representing about 6% of all human cancers. Human papillomaviruses (HPV) infect the cervical epithelium and maintain themselves in a latent phase in the basal layer of cells as extrachromosomal plasmids, which replicate in step with the chromosomes. Infectious virus particles are generated through a switch to a replicative phase in the outer epithelial layers, as progeny of these cells begin to differentiate before being sloughed from the surface. Here, cell division should normally stop, but the virus interferes with this cell-cycle arrest so as to allow replication of its own genome. Usually, the effect is restricted to the outer layers of cells and is relatively harmless, as in a wart. Occasionally, however, a genetic accident causes the


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Cell_Biology_Alberts. to allow replication of its own genome. Usually, the effect is restricted to the outer layers of cells and is relatively harmless, as in a wart. Occasionally, however, a genetic accident causes the viral genes that encode the proteins that prevent cell-cycle arrest to integrate into the host chromosome and become active in the basal layer, where the stem cells of the epithelium reside (see Figure 22–10). This can lead to cancer, with the viral genes acting as oncogenes (Figure 20–40).


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Cell_Biology_Alberts. The whole process, from initial infection to invasive cancer, is slow, taking many years. It involves a long intermediate stage when the affected patch of cervical epithelium is visibly disordered but the cells have not yet begun to invade the underlying connective tissue—a phenomenon called intraepithelial neoplasia. Many such lesions regress spontaneously. Moreover, at this stage, it is still easy to cure the condition by destroying or surgically removing the abnormal tissue. Fortunately, 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).


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Cell_Biology_Alberts. Better still, a vaccine has now been developed that protects against infection with the relevant strains of human papillomavirus. This vaccine, given to girls before puberty and thus before they become sexually active, has been shown to greatly reduce their risk of ever developing cervical cancer. Because the virus spreads through sexual activity, it is now recommended that both young males and young females be routinely vaccinated. Mass immunization programs have begun in several countries.


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Cell_Biology_Alberts. Figure 20–40 How certain papillomaviruses are thought to give rise to cancer of the uterine cervix. Papillomaviruses have double-stranded circular DNA chromosomes of about 8000 nucleotide pairs. These chromosomes are normally stably maintained in the basal cells of the epithelium as plasmids (red circles), whose replication is regulated so as to keep step with the chromosomes of the host. (A) Normally, the virus perturbs the host cell cycle only when the virus is programmed to produce infectious progeny, in the outer layers of an epithelium. This is relatively harmless.


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Cell_Biology_Alberts. (B) Rare accidents can cause the integration of a fragment of such a plasmid into a chromosome of the host, altering the environment of the viral genes in the basal cells of an epithelium. This can disrupt the normal control of viral gene expression. The unregulated production of certain viral proteins (E6 and E7) interferes with the control of cell division in the basal cells, thereby helping to generate a cancer (bottom). viral proteins mediate the controlled replication of the virus in outer cell layers unregulated production of viral proteins drives cell proliferation in basal cell layer Infectious Agents Can Cause Cancer in a Variety of Ways


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Cell_Biology_Alberts. Infectious Agents Can Cause Cancer in a Variety of Ways In papillomaviruses, the viral genes that are mainly to blame are called E6 and E7. The protein products of these viral oncogenes interact with many host-cell proteins, but, in particular, they bind to two key tumor suppressor proteins of the host cell, putting them both out of action and so permitting the cell to replicate its DNA and divide in an uncontrolled way. One of these host proteins is Rb; the other is p53. Other DNA tumor viruses use similar mechanisms to inhibit Rb and p53, underlining the central importance of inactivating both of these tumor suppressor pathways if a cell is to escape the normal constraints on proliferation.


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Cell_Biology_Alberts. In other cancers, viruses have indirect tumor-promoting actions. The hepatitis-B and C viruses, for example, favor the development of liver cancer by causing chronic inflammation (hepatitis), which stimulates an extensive cell division in the liver that promotes the eventual evolution of tumor cells. In AIDS, the human immunodeficiency virus (HIV) promotes development of an otherwise rare cancer called Kaposi’s sarcoma by destroying the immune system, thereby permitting a secondary infection with a human herpesvirus (HHV-8) that has a direct carcinogenic action. By causing severe inflammation, chronic infection with parasites and bacteria can also promote the development of some cancers. For example, chronic infection of the stomach with the bacterium Helicobacter pylori, which causes ulcers, appears to be a major cause of stomach cancer; dramatic falls in the incidence of stomach cancer over the last half-century (see Figure 20–39) correlate with a decline in the incidence of


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Cell_Biology_Alberts. ulcers, appears to be a major cause of stomach cancer; dramatic falls in the incidence of stomach cancer over the last half-century (see Figure 20–39) correlate with a decline in the incidence of Helicobacter infections.


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Cell_Biology_Alberts. The Search for Cancer Cures Is Difficult but Not hopeless The difficulty of curing a cancer is similar to the difficulty of getting rid of weeds. Cancer cells can be removed surgically or destroyed with toxic chemicals or radiation, but it is hard to eradicate every single one of them. Surgery can rarely ferret out every metastasis, and treatments that kill cancer cells are generally toxic to normal cells as well. Moreover, unlike normal cells, cancer cells can mutate rapidly and will often evolve resistance to the poisons and irradiation used against them.


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Cell_Biology_Alberts. In spite of these difficulties, effective cures using anticancer drugs (alone or in combination with other treatments) have already been found for some formerly highly lethal cancers, including Hodgkin’s lymphoma, testicular cancer, choriocarcinoma, and some leukemias and other cancers of childhood. Even for types of cancer where a cure at present seems beyond our reach, there are treatments that will prolong life or at least relieve distress. But what prospect is there of doing better and finding cures for the most common forms of cancer, which still cause great suffering and so many deaths? Traditional Therapies Exploit the Genetic Instability and Loss of Cell-Cycle Checkpoint Responses in Cancer Cells


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Cell_Biology_Alberts. Anticancer therapies need to take advantage of some molecular peculiarity of cancer cells that distinguishes them from normal cells. One such property is genetic instability, reflecting deficiencies in chromosome maintenance, cell-cycle checkpoints, and/or DNA repair. Remarkably, the most widely used cancer therapies seem to work by exploiting these abnormalities, although this was not known by the scientists who first developed the treatments. Ionizing radiation and most anticancer drugs damage DNA or interfere with chromosome segregation at mitosis, and they preferentially kill cancer cells because cancer cells have a diminished ability to survive the damage. Normal cells treated with radiation, for example, arrest their cell cycle until they have repaired the damage to their DNA, thanks to the cell-cycle checkpoint responses discussed in Chapter 17. Because cancer cells generally have defects in their checkpoint responses, they may continue to divide after irradiation, only to die


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Cell_Biology_Alberts. to the cell-cycle checkpoint responses discussed in Chapter 17. Because cancer cells generally have defects in their checkpoint responses, they may continue to divide after irradiation, only to die after a few days because the genetic damage remains unrepaired. More generally, most cancer cells are physiologically deranged to a stressful degree: they live dangerously. Even though the cells in a tumor have evolved to be unusually tolerant of minor DNA damage, they are hypersensitive to the much greater amount of damage that can be created by radiation and by DNA-damaging drugs. A small increase of genetic damage can be enough to tip the balance between proliferation and death.


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Cell_Biology_Alberts. Unfortunately, while the molecular defects present in cancer cells often enhance their sensitivity to cytotoxic agents, they can also increase their resistance. For example, where a normal cell might die by apoptosis in response to DNA damage, thanks to the stress response mediated by p53, a cancer cell may escape apoptosis because its p53 is lacking. Cancers vary widely in their sensitivity to cytotoxic treatments, some responding to one drug, some to another, probably reflecting the particular kinds of defects that a particular cancer has in DNA repair, cell-cycle checkpoints, and the control of apoptosis.


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Cell_Biology_Alberts. Radiotherapy and traditional cytotoxic drugs are rather weakly selective: they hurt normal cells as well as the cancer cells, and the safety margin is narrow. The dose often cannot be raised high enough to kill all the cancer cells, because this would kill the patient, and curative treatments, where achievable, generally require a combination of several cytotoxic agents. The side effects can be harsh and hard to endure. How can we do better?


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Cell_Biology_Alberts. An ideal treatment is one that is cell-lethal in combination with some lesion that is present in the cancer cells, but harmless to cells where this lesion is absent. Such a treatment is said to be synthetic-lethal (from the original sense of the word synthesis, meaning “putting together”): it kills only in partnership with the cancer-specific mutation. As we become increasingly able to pinpoint the specific alterations in cancer cells that make them different from their normal neighbors, new opportunities for such precisely targeted treatments are coming into view. We end this chapter with some examples of new treatments of this type that are already being put into practice.


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Cell_Biology_Alberts. As we have emphasized, the genetic instability of cancer cells makes the cells both dangerous and vulnerable—dangerous because of the enhancement in their ability to evolve and proliferate, and vulnerable because treatment that leads to still more extreme genetic disruption can take them over the brink and kill them. In some cancers, genetic instability results from an identified fault in one of the many devices on which normal cells depend for DNA repair and maintenance. In this case, a drug is tailored to block a complementary part of the DNA repair machinery can lead to such severe genetic damage that the cancer cells die.


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Cell_Biology_Alberts. Detailed studies of the mechanisms for DNA maintenance discussed in Chapter 5 reveal a surprising amount of apparent redundancy. Thus, knocking out a particular pathway for DNA repair is generally less disastrous than one might expect, because alternate repair pathways exist. For example, stalled DNA replication forks can arise when the fork encounters a single-strand break in a template strand, but cells can avoid the disaster that would otherwise result either by directly repairing these single-strand breaks, or, if that fails, repairing the broken fork that results by homologous recombination (see Figure 5–50). Suppose that the cells in a particular cancer have become genetically unstable by acquiring a mutation that reduces their ability to repair broken replication forks by homologous recombination. Might it be possible to eradicate that cancer by treating it with a drug that inhibits the repair of single-strand breaks, thereby greatly increasing the number of forks that break?


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Cell_Biology_Alberts. recombination. Might it be possible to eradicate that cancer by treating it with a drug that inhibits the repair of single-strand breaks, thereby greatly increasing the number of forks that break? The consequences of such drug treatment might be expected to be relatively harmless for normal cells, but lethal for the cancer.


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Cell_Biology_Alberts. This strategy appears to work to kill the cells in at least one class of cancers— those that have inactivated both copies of either their Brca1 or their Brca2 tumor continues, due to permanently suppressor genes. As described in Chapter 5, Brca2 is an accessory protein that interacts with the Rad51 protein (the RecA analog in humans) in the repair of DNA double-strand breaks by homologous recombination. Brca1 is another protein that is also required for this repair process. Like Rb, the Brca1 and Brca2 genes were discovered as mutations that predispose humans to cancer—in this case, chiefly cancers of the breast and ovaries (though unlike Rb, they seem to be involved in only a small proportion of such cancers). Individuals who inherit one mutant copy of Brca1 or Brca2 develop tumors that have inactivated the second copy of the same gene, presumably because this change makes the cells genetically unstable and speeds tumor progression.


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Cell_Biology_Alberts. While Brca1 and Brca2 are needed for the repair of DNA double-strand breaks, single-strand breaks are repaired by other machinery, involving an enzyme called PARP (polyADP-ribose polymerase). This understanding of the basic mechanisms of DNA repair led to a striking discovery: drugs that block PARP activity kill Brca-deficient cells with extraordinary selectivity. At the same time, PARP inhibition has very little effect on normal cells; in fact, mice that have been engineered to lack PARP1—the major PARP family member involved in DNA repair—remain healthy under laboratory conditions. This result suggests that, while the repair pathway requiring PARP provides a first line of defense against persistent breaks in a DNA strand, these breaks can be repaired efficiently by a genetic recombination pathway in normal cells. In contrast, tumor cells that have acquired their genetic instability by the loss of Brca1 or Brca2 have lost this second line of defense, and they are therefore uniquely


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Cell_Biology_Alberts. pathway in normal cells. In contrast, tumor cells that have acquired their genetic instability by the loss of Brca1 or Brca2 have lost this second line of defense, and they are therefore uniquely sensitive to PARP inhibitors (Figure 20–41).


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Cell_Biology_Alberts. PARP inhibitors are still under clinical trial, but they have produced some striking results, causing tumors to regress in many Brca-deficient patients and delaying progression of their disease, with relatively few disagreeable side effects. These drugs also appear to be applicable to cancers with other mutations that cause defects in the cell’s homologous recombination machinery—a small, though significant, proportion of cancer cases.


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Cell_Biology_Alberts. Figure 20–41 How a tumor’s genetic instability can be exploited for cancer therapy. As explained in Chapter 5, the maintenance of DNA sequences is so critical for life that cells have evolved multiple pathways for repairing DNA damage and reducing DNA replication errors. As illustrated, a DNA replication fork will stall whenever it encounters a break in a DNA template strand. In this example, normal cells have two different repair pathways that help them to avoid the problem, pathways 1 and 2. They are therefore not harmed by treatment with a drug that blocks repair pathway 1. But, because the inactivation of repair pathway 2 was selected for during the evolution of the tumor cell, the tumor cells are killed by the same drug treatment.


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Cell_Biology_Alberts. In the actual case that underlies this example, the function of repair pathway 1 (requiring the PARP protein discussed in the text) is to remove persistent, accidental breaks in a DNA single strand before they are encountered by a moving replication fork. Pathway 2 is the recombination-dependent process (requiring the Brca2 and Brca1 proteins) for repairing stalled replication forks illustrated in Figure 5–50. PARP inhibitors have promise for treating cancers with defective Brca2 or Brca1 tumor suppressor genes. PARP inhibition provides an example of the type of rational, highly selective approach to cancer therapy that is beginning to be possible. Along with other new treatments to be discussed below, it raises high hopes for treating many other cancers. Small Molecules Can Be Designed to Inhibit Specific Oncogenic Proteins


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Cell_Biology_Alberts. An obvious tactic for treating cancer is to attack a tumor expressing an oncogene with a drug designed to specifically block the function of the protein that the oncogene produces. But how can such a treatment avoid hurting the normal cells that depend on the function of the proto-oncogene from which the oncogene has evolved, and why should the drug kill the cancer cells, rather than simply calm them down? One answer may lie in the phenomenon of oncogene dependence. Once a cancer cell has undergone an oncogenic mutation, it will often undergo further mutations, epigenetic changes, or physiological adaptations that make it reliant on the hyperactivity of the initial oncogene, just as drug addicts become reliant on high doses of their drug. Blocking the activity of the oncogenic protein may then kill the cancer cell without significantly harming its normal neighbors. Some remarkable successes have been achieved in this way.


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Cell_Biology_Alberts. As we saw earlier, chronic myelogenous leukemia (CML) is usually associated with a particular chromosomal translocation, visible as the Philadelphia chromosome (see Figure 20–5). This results from chromosome breakage and rejoining at the sites of two specific genes, Abl and Bcr. The fusion of these genes creates a hybrid gene, called Bcr-Abl, that codes for a chimeric protein consisting of the N-terminal fragment of Bcr fused to the C-terminal portion of Abl (Figure 20–42). Abl is a tyrosine kinase involved in cell signaling. The substitution of the Bcr fragment for the normal N-terminus of Abl makes it hyperactive, so that it stimulates inappropriate proliferation of the hemopoietic precursor cells that contain it and prevents these cells from dying by apoptosis—which many of them would normally do. As a result, excessive numbers of white blood cells accumulate in the bloodstream, producing CML.


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Cell_Biology_Alberts. The chimeric Bcr-Abl protein is an obvious target for therapeutic attack. Searches for synthetic drug molecules that can inhibit the activity of tyrosine kinases discovered one, called imatinib (trade name Gleevec®), that blocks Bcr-Abl (Figure 20–43). When the drug was first given to patients with CML, nearly all of them showed a dramatic response, with an apparent disappearance of the cells carrying the Philadelphia chromosome in over 80% of patients. The response appears relatively durable: after years of continuous treatment, many patients have not progressed to later stages of the disease—although imatinib-resistant cancers emerge with a probability of about 5% per year during the early years.


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Cell_Biology_Alberts. Figure 20–42 The conversion of the Abl proto-oncogene into an oncogene in patients with chronic myelogenous leukemia. The chromosome translocation responsible joins the Bcr gene on chromosome 22 to the Abl gene from chromosome 9, thereby generating a Philadelphia chromosome (see Figure 20–5). The resulting fusion protein has the N-terminus of the Bcr protein joined to the C-terminus of the Abl tyrosine protein kinase; in consequence, the Abl kinase domain becomes inappropriately active, driving excessive proliferation of a clone of hemopoietic cells in the bone marrow. Figure 20–43 How imatinib (Gleevec) blocks the activity of Bcr-Abl protein and halts chronic myelogenous leukemia.


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Cell_Biology_Alberts. Figure 20–43 How imatinib (Gleevec) blocks the activity of Bcr-Abl protein and halts chronic myelogenous leukemia. (A) Imatinib sits in the ATP-binding pocket of the tyrosine kinase domain of Bcr-Abl and thereby prevents Bcr-Abl from transferring a phosphate group from ATP onto a tyrosine residue in a substrate protein. This blocks transmission of a signal for cell proliferation and survival. (B) The structure of the complex of imatinib (solid blue object) with the tyrosine kinase domain of the Abl protein (ribbon diagram), as determined by x-ray crystallography. (C) The chemical structure of the drug. It can be given by mouth; it has side effects, but they are usually quite tolerable. (B, from T. Schindler et al., Science 289:1938–1942, 2000. With permission from AAAS.)


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Cell_Biology_Alberts. Results are not so good for those patients who have already progressed to the more acute phase of myeloid leukemia, known as blast crisis, where genetic instability has set in and the march of the disease is far more rapid. These patients show a response at first and then relapse because the cancer cells develop a resistance to imatinib. This resistance is usually associated with secondary mutations in the part of the Bcr-Abl gene that encodes the kinase domain, disrupting the ability of imatinib to bind to Bcr-Abl kinase. Second-generation inhibitors that function effectively against a whole range of imatinib-resistant mutants have now been developed. By combining one or more of these new inhibitors with imatinib as the initial therapy (see below), it seems that CML—at least in the chronic (early) stage—may be on its way to becoming a curable disease.


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Cell_Biology_Alberts. Despite the complications with resistance, the extraordinary success of imatinib is enough to drive home an important principle: once we understand precisely what genetic lesions have occurred in a cancer, we can begin to design effective rational methods to treat it. This success story has fueled efforts to identify small-molecule inhibitors for other oncogenic protein kinases and to use them to attack the appropriate cancer cells. Increasing numbers are being developed. These include molecules that target the EGF receptor and are currently approved for the treatment of some lung cancers, as well as drugs that specifically target the B-Raf oncoprotein in melanomas.


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Cell_Biology_Alberts. Protein kinases have been relatively easy to inhibit with small molecules like imatinib, and many kinase inhibitors are being produced by pharmaceutical companies in the hope that they can be effective as drugs for some forms of cancer. Many cancers lack an oncogenic mutation in a protein kinase. But most tumors contain inappropriately activated signaling pathways, for which a target somewhere in the pathway can hopefully be found (Movie 20.7). As an example, Figure 20–44 displays some of the anticancer drugs and drug targets that are currently being tested for a pathway frequently activated in cancers. Many Cancers May Be Treatable by Enhancing the Immune Response Against the Specific Tumor


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Cell_Biology_Alberts. Many Cancers May Be Treatable by Enhancing the Immune Response Against the Specific Tumor Cancers have complex interactions with the immune system, and its various components may sometimes help as well as hinder tumor progression. But for more than a century it has been a dream of cancer researchers to somehow harness the immune system in a controlled and efficient way to exterminate cancer cells, just as it exterminates infectious organisms. There are finally signs that this dream may one day be realized, at least for some forms of cancer.


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Cell_Biology_Alberts. The simplest type of immunological therapy, conceptually at least, is to inject the patient with antibodies that target the cancer cells. This approach has had some successes. About 25% of breast cancers, for example, express unusually high levels of the Her2 protein, a receptor tyrosine kinase related to the EGF receptor that plays a part in the normal development of mammary epithelium. A monoclonal antibody called trastuzumab (trade name Herceptin®) that binds to Her2 and inhibits its function slows the growth of breast tumors in humans that overexpress Her2, and it is now an approved therapy for these cancers (see Figure 20–44). A related approach uses antibodies to deliver poisons to the cancer cells. Antibodies against proteins that are abundant on the surface of a particular type of cancer cell but rare on normal cells can be armed with a toxin that kills those cells that bind the antibody molecule.


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Cell_Biology_Alberts. A great deal of current excitement centers around a different type of approach, based on the relatively recent recognition that the microenvironment in a tumor is highly immunosuppressive. As a result, the cancer victim’s immune system is prevented from destroying the tumor cells. Recall that, from the thousands of genome sequences thus far determined, we know that a typical cancer cell will contain on the order of 50 proteins with a mutation that alters an amino acid sequence, most of these being “passenger” mutations, as previously explained (see p. 1104). Many of these mutant proteins will be recognized by the patient’s immune system as foreign, but—to allow the cancer cells to survive throughout the course of tumor progression—the cancer cells have evolved a set of anti-immune defenses. These


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Cell_Biology_Alberts. Figure 20–44 Some anticancer drugs and drug targets in the Ras–MAP-kinase signaling pathway. Each of the signaling proteins in this diagram has been identified as a product of a cancer-critical gene, with the exception of Raf1 and Erk. This Ras– MAP-kinase signaling pathway is triggered by a variety of receptor tyrosine kinases (RTKs), including the EGF receptor (see Figures 15–47 and 15–49). Those drugs that are antibodies end in “mab,” while those that are small molecules end in “nib.” (Adapted from B. Vogelstein et al, Science 339:1546–1558, 2013.) defenses include the expression on the cancer cell surface of one or more proteins that bind to inhibitory receptors on activated T cells.


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Cell_Biology_Alberts. The normal immune system is subject to complex controls that keep its activity within safe bounds and prevent autoimmunity from developing. The inhibitory receptors that are expressed on the surface of activated T cells have an important normal function: they control the immune response by down-regulating the T cell response under appropriate circumstances. But in the context of a tumor, the down-regulation is inappropriate, because it prevents the organism from killing the cancer cells that are threatening its survival.


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Cell_Biology_Alberts. In its attack on infectious organisms, the natural immune system usually eliminates every last trace of infection and maintains this immunity in the long term. The challenge is to find ways of recruiting the immune system to attack cancers with similar efficiency and specificity, hunting the cancer cells down by virtue of the tumor-specific antigens that they express. With this aim, a new type of anticancer therapy focuses on overcoming the immunosuppressive environment in a tumor through the use of specific antibodies that prevent the tumor cells from engaging with the inhibitory receptors on T cells. As illustrated in Figure 20–45A, blocking the action of the immune suppressors with such treatments should unleash an immune attack on the cancer cells. Importantly, multiple antigens are recognized as foreign; thus, the cancer cells cannot escape through the mutational loss of a single antigen, making it difficult for the tumor to escape from the T cell attack.


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Cell_Biology_Alberts. This is a potentially dangerous strategy. If one provokes the immune system to recognize the cancer cells as targets for destruction, there is a risk of autoimmune side effects with dire consequences for normal tissues of the body, since the cancer cells and the normal cells are close cousins and share most of their molecular features. Nevertheless, several recent successes seem to hold great promise for the future.


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Cell_Biology_Alberts. One of the many molecules involved in keeping the activity of the normal immune system within safe bounds is a protein called CTLA4 (cytotoxic T-lymphocyte-associated protein 4), which functions as an inhibitory receptor on the surface of T cells. If the function of CTLA4 is blocked, the T cells become more reactive and may mount an attack on cells that they would otherwise leave in peace. In particular, the T cells may attack tumor cells that are recognizably abnormal but whose presence was previously tolerated. With this in mind, cancer immunologists developed a monoclonal antibody, called ipilimumab, that binds to CTLA4 and blocks its action. Injected repeatedly into patients with metastatic melanoma, this antibody increases their median lifespan by several months and, in one large trial, enabled as many as a quarter of them to survive for five years


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Cell_Biology_Alberts. Figure 20–45 Therapies designed to remove the immunosuppressive microenvironment in tumors. (A) The cells in tumors will produce many mutant proteins. As described in Chapter 24, peptides from these proteins will be displayed on MhC complexes on the tumor-cell surface and would normally activate a T cell response that destroys the tumor (see Figure 24–42). however, as schematically illustrated, during the course of tumor progression, the cancer cells have evolved immunosuppressive mechanisms that protect them from such killing. (B) The cells in tumors often protect themselves from immune attack by expressing proteins on their surface that bind to and thereby activate the inhibitory receptors on T cells. As indicated, this makes the tumor susceptible to specific antibody therapies. In this diagram, two such inhibitory receptors are shown, PD1 and a hypothetical protein X. Different tumors are thought to protect themselves by activating different members of a large set of T cell


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Cell_Biology_Alberts. In this diagram, two such inhibitory receptors are shown, PD1 and a hypothetical protein X. Different tumors are thought to protect themselves by activating different members of a large set of T cell inhibitory receptors, some of which are not yet well characterized.


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Cell_Biology_Alberts. or more—far beyond expectations for comparable patients without this treatment. Even more promising are recent clinical trials using a combination of two antibodies, one against CTLA4 and the other against PD1, a second cell-surface receptor on T cells that normally restrains their activity.


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Cell_Biology_Alberts. In clinical trials using such techniques, a substantial fraction of the patients can respond in a dramatic way, with their cancer being driven into remission for years, while the treatment fails to help others with the same type of cancer. One possible explanation is that, while most tumors express proteins that protect them from T-cell attack, these proteins are different for different tumors. Thus, while some tumors will respond dramatically when treated with an antibody that blocks a particular immunosuppressive agent, many others will not. If true, one can foresee an era of personalized immunotherapy, in which each patient’s tumor is molecularly analyzed to determine its particular mechanisms of immunosuppression. The patient would then be treated with a specific cocktail of antibodies designed to remove these blocks (see Figure 20–45). Cancers Evolve Resistance to Therapies


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Cell_Biology_Alberts. Cancers Evolve Resistance to Therapies High hopes have to be tempered with sobering realities. We have seen that genetic instability can provide an Achilles heel that cancer therapies can exploit, but at the same time it can make eradicating the disease more difficult by allowing the cancer cells to evolve resistance to therapeutic drugs, often at an alarming rate. This applies even to the drugs that target genetic instability itself. Thus, PARP inhibitors give valuable remission of illness, but in the long term the disease generally comes back. For example, Brca-deficient cancers can sometimes develop resistance to PARP inhibitors by undergoing a second mutation in an affected Brca gene that restores its function. By then, the cancer is already out of control and it may be too late to affect the course of the disease with additional treatments.


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Cell_Biology_Alberts. There are many different strategies by which cancers can evolve resistance to anticancer drugs. Often, a cancer will be dramatically reduced in size by an initial drug treatment, with all of the detectable tumor cells seeming to disappear. But months or years later the cancer will reappear in an altered form that is resistant to the drug that was at first so successful. In such cases, the initial drug treatment has evidently failed to destroy some tiny fraction of cells in the original tumor-cell population. These cells have escaped death because they carry a protective mutation or epigenetic change, or perhaps simply because they were lurking in a protected environment. They eventually regenerate the cancer by continuing to proliferate, mutating and evolving still further as they do so.


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Cell_Biology_Alberts. In some cases, cells that are exposed to one anticancer drug evolve a resistance not only to that drug but also to other drugs to which they have never been exposed. This phenomenon of multidrug resistance frequently correlates with amplification of a part of the genome that contains a gene called Mdr1 or Abcb1. This gene encodes a plasma-membrane-bound transport ATPase of the ABC transporter superfamily (discussed in Chapter 11), which pumps lipophilic drugs out of the cell (see Movie 11.5). The overproduction of this protein (or some of its other family members) by a cancer cell can prevent the intracellular accumulation of many cytotoxic drugs, making the cell insensitive to them.


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Cell_Biology_Alberts. In the to-and-fro struggle between advanced metastatic cancer and the therapist, as current practice stands, the cancer usually wins in the end. Does it have to be so? As we discuss below, there is reason to think that by attacking a cancer with many weapons at once—instead of using them one after another, each until it fails—it may be possible to do much better. Combination Therapies May Succeed Where Treatments with One Drug at a Time Fail Nowadays, cancers caught at an early stage can often be cured, by surgery, radiation, or drugs. For most cancers that have progressed and metastasized widely, however, cure is still beyond us. Treatments such as those described above can no cell is resistant CANCER CURED = cell resistant to Ato both drugs = cell resistant to A and B (B) give valuable remissions, but sooner or later these are typically followed by relapse.


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Cell_Biology_Alberts. Nevertheless, for some relatively rare forms of advanced cancer, curative therapies have been developed. These generally involve a cocktail of several different anticancer agents: by trial and error, certain combinations of cytotoxic drugs have been found to wipe out the cancer completely. Discovering such combinations has hitherto involved a long, hard search. But now, armed with our new tools for identifying the specific genetic lesions that cancer cells contain, the prospects are better.


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Cell_Biology_Alberts. The logic of combination therapies is the same as that behind the current treatment of HIV-AIDS with a cocktail of three different protease inhibitors: whereas there may always be some cells in the initial population carrying the rare mutations that confer resistance to any one drug treatment, there should be no cell carrying the whole set of rare mutations that would confer resistance to several different drugs delivered simultaneously. In contrast, sequential drug treatments will allow the few cells resistant to the first drug to multiply to large numbers. Within this large population of cells resistant to the first drug, a small number of cells are likely to have arisen that are resistant to the next drug also; and so on (Figure 20–46). We Now have the Tools to Devise Combination Therapies Tailored to the Individual Patient


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Cell_Biology_Alberts. We Now have the Tools to Devise Combination Therapies Tailored to the Individual Patient Efficient, rational combination drug therapy requires three things. First, we have to identify multiple peculiarities of cancer cells that make them vulnerable in ways that normal cells are not. Second, we have to devise drugs (or other treatments) that target each of these vulnerabilities. Third, we have to match the combination of drugs to the specific set of peculiarities present in the cancer cells of the individual patient.


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Cell_Biology_Alberts. The first requirement is already partially met: we now have large catalogs of cancer-critical genes that are commonly mutated in cancer cells. The second requirement is harder, but attainable: we have described some remarkable recent successes, and for cancer researchers there is excitement in the air. It is becoming increasingly possible to use our growing knowledge of cell and molecular biology to design new drugs against designated targets. At the same time, efficient, high-throughput automated methods are available to screen large libraries of chemicals for any that may be effective against cells with a given cancer-related defect. In such searches, the goal is synthetic lethality: a cell death that occurs when and only when a particular drug is put together with a particular cancer cell abnormality. Through these and other approaches, the repertoire of precisely targeted anticancer drugs is rapidly increasing.


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Cell_Biology_Alberts. Figure 20–46 Why multidrug treatments can be more effective than sequential treatments for cancer therapy. (A) Because tumor cells are hypermutable, two single-drug treatments that are given sequentially often allow for the selection of mutant cell clones that are resistant to both drugs. (B) Simultaneous treatment with both drugs can be more effective.


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Cell_Biology_Alberts. This brings us to the third requirement: the therapy—the choice of drugs to be given in combination—must be tailored to the individual patient. Here, too, the prospects are bright. Cancers evolve by a fundamentally random process, and each patient is different; but modern methods of genome analysis now let us characterize the cells from a tumor biopsy in exhaustive detail so as to discover which cancer-critical genes are affected in a particular case. Admittedly, this is not straightforward: the tumor cells in an individual patient are heterogeneous and do not all contain the same genetic lesions. With increased understandings of the pathways of cancer evolution, however, and with the experience gained from many different cases, it should become possible to make good guesses at the optimal therapies to use.


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Cell_Biology_Alberts. From the perspective of the patient, the pace of advance in cancer research can seem frustratingly slow. Each new drug has to be tested in the clinic, first for safety and then for efficacy, before it can be released for general use. And if the drug is to be used in combination with others, the combination therapy must then go through the same long process. Strict ethical rules constrain the conduct of trials, which means that they take time—typically several years. But slow and cautious steps, taken systematically in the right direction, can lead to great advances. There is still far to go, but the examples that we have discussed provide proof of principle and grounds for optimism. From the cancer research effort, we have learned a great deal of what we know about the molecular biology of the normal cell. Now, more and more, we are discovering how to put that knowledge to use in the battle with cancer itself.


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Cell_Biology_Alberts. Our growing understanding of the cell biology of cancers has already begun to lead to better ways of preventing, diagnosing, and treating these diseases. Anticancer therapies can be designed to destroy cancer cells preferentially by exploiting the properties that distinguish cancer cells from normal cells, including the cancer cells’ dependence on oncogenic proteins and the defects they harbor in their DNA repair mechanisms. We now have good evidence that, by increasing our understanding of normal cell control mechanisms and exactly how they are subverted in specific cancers, we can eventually devise drugs to kill cancers precisely by attacking specific molecules critical for the growth and survival of the cancer cells. In addition, great progress has recently been made through sophisticated immunological approaches to cancer therapy. And, as we become better able to determine which genes are altered in the cells of any given tumor, we can begin to tailor treatments more accurately to


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Cell_Biology_Alberts. immunological approaches to cancer therapy. And, as we become better able to determine which genes are altered in the cells of any given tumor, we can begin to tailor treatments more accurately to each individual patient.


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Cell_Biology_Alberts. Which statements are true? Explain why or why not. What is required to enable a cancer cell to metastasize? how can the molecular analysis of an individual tumor be more effectively used to design effective therapies to kill it? Can we identify general features common to all cancer cells—such as their production of misfolded, mutated proteins—that can be used for the targeted destruction of many different types of cancers? Can sensitive and reliable blood tests be devised to detect cancers very early, before they have grown to a size where treatment with a single drug will generally be defeated by the survival of a preexisting resistant variant? how can the observed environmental effects on cancer rates be exploited to reduce avoidable cancers? Can new technologies be devised to reveal exactly how a quiescent micrometastasis converts to a full-blown metastatic tumor?


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Cell_Biology_Alberts. Can new technologies be devised to reveal exactly how a quiescent micrometastasis converts to a full-blown metastatic tumor? 20–1 The chemical carcinogen dimethylbenz[a]anthra-20–4 The main environmental causes of cancer are the cene (DMBA) must be an extraordinarily specific mutagen products of our highly industrialized way of life such as since 90% of the skin tumors it causes have an A-to-T alter-pollution and food additives. ation at exactly the same site in the mutant Ras gene.


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Cell_Biology_Alberts. Discuss the following problems. 20–2 In the cellular regulatory pathways that control 20–5 In contrast to colon cancer, whose incidence cell growth and proliferation, the products of oncogenes increases dramatically with age, incidence of osteosarare stimulatory components and the products of tumor coma—a tumor that occurs most commonly in the long suppressor genes are inhibitory components. bones—peaks during adolescence. Osteosarcomas are rel atively rare in young children (up to age 9) and in adults 20–3 Cancer therapies directed solely at killing the rap-(over 20). Why do you suppose that the incidence of osteoidly dividing cells that make up the bulk of a tumor are sarcoma does not show the same sort of age-dependence unlikely to eliminate the cancer from many patients. as colon cancer? lung cancer mortality, cumulative risk (%)


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Cell_Biology_Alberts. lung cancer mortality, cumulative risk (%) Figure Q20–1 Cumulative risk of lung cancer mortality for nonsmokers, smokers, and former smokers (Problem 20–6). Cumulative risk is the running total of deaths, as a percentage, for each group. Thus, for continuing smokers, 1% died of lung cancer risk of 5%); and 11% more cumulative risk of 16%). 20–6 Mortality due to lung cancer was followed in groups of males in the United Kingdom for 50 years. Figure Q20–1 shows the cumulative risk of dying from lung cancer as a function of age and smoking habits for four groups of males: those who never smoked, those who stopped at age 30, those who stopped at age 50, and those who continued to smoke. These data show clearly that individuals can substantially reduce their cumulative risk of dying from lung cancer by stopping smoking. What do you suppose is the biological basis for this observation?


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Cell_Biology_Alberts. 20–7 A small fraction—2 to 3%—of all cancers, across many subtypes, displays a quite remarkable phenomenon: tens to hundreds of rearrangements that primarily involve a single chromosome, or chromosomal region. The breakpoints can be tightly clustered, with several in a few kilobases; the junctions of the rearrangements often involve segments of DNA that were not originally close together on the chromosome. The copy number of various segments within the rearranged chromosome was found to be either zero, indicating deletion, or one, indicating retention. You can imagine two ways in which such multiple, localized rearrangements might happen: a progressive rearrangements model with ongoing inversions, deletions, and duplications involving a localized area, or a catastrophic model in which the chromosome is shattered into fragments that are stitched back together in random order by nonhomologous end joining (Figure Q20–2).


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Cell_Biology_Alberts. A. Which of the two models in Figure Q20–2 accounts more readily for the features of these highly rearranged chromosomes? Explain your reasoning. B. For whichever model you choose, suggest how such multiple rearrangements might arise. (The true mechanism is not known.) C. Do you suppose such rearrangements are likely to be causative events in the cancers in which they are found, or are they probably just passenger events that are unrelated to the cancer? If you think they could be driver events, suggest how such rearrangements might activate an oncogene or inactivate a tumor suppressor gene. 20–8 Virtually all cancer treatments are designed to kill cancer cells, usually by inducing apoptosis. However, one particular cancer—acute promyelocytic leukemia (APL)— has been successfully treated with all-trans-retinoic acid, which causes the promyelocytes to differentiate into neutrophils. How might a change in the state of differentiation of APL cancer cells help the patient?


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Cell_Biology_Alberts. 20–9 One major goal of modern cancer therapy is to identify small molecules—anticancer drugs—that can be used to inhibit the products of specific cancer-critical genes. If you were searching for such molecules, would you design inhibitors for the products of oncogenes or the products of tumor suppressor genes? Explain why you would (or would not) select each type of gene. (lost to cell) Figure Q20–2 Two models to explain the multiple, localized chromosome rearrangements found in some cancers (Problem 20–7). The progressive rearrangements model shows a sequence of rearrangements that disrupts the chromosome, generating increasingly complex chromosomal configurations. The chromosome catastrophe model shows the chromosome being fragmented and then reassembled randomly, with some pieces left out.


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Cell_Biology_Alberts. 20–10 PolyADP-ribose polymerase (PARP) plays a key role in the repair of DNA single-strand breaks. In the presence of the PARP inhibitor olaparib, single-strand breaks accumulate. When a replication fork encounters a sin-gle-strand break, it converts it to a double-strand break, which in normal cells is then repaired by homologous recombination. In cells defective for homologous recombination, however, inhibition of PARP triggers cell death. Patients who have only one functional copy of the Brca1 gene, which is required for homologous recombination, are at much higher risk for cancer of the breast and ovary. Cancers that arise in these tissues in these patients can be treated successfully with olaparib. Explain how it is that treatment with olaparib kills the cancer cells in these patients, but does not harm their normal cells.


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Cell_Biology_Alberts. 20–11 The Tasmanian devil, a carnivorous Australian marsupial, is threatened with extinction by the spread of a fatal disease in which a malignant oral–facial tumor interferes with the animal’s ability to feed. You have been called in to analyze the source of this unusual cancer. It seems clear to you that the cancer is somehow spread from devil to devil, very likely by their frequent fighting, which is accompanied by biting around the face and mouth. To uncover the source of the cancer, you isolate tumors from 11 devils captured in widely separated regions and examine them. As might be expected, the karyotypes of the tumor cells are highly rearranged relative to that of the wild-type devil (Figure Q20–3). Surprisingly, you find that the karyotypes from all 11 tumor samples are very similar. Moreover, one of the Tasmanian devils has an inversion on chromosome 5 that is not present in its facial tumor. How do you suppose this cancer is transmitted from devil to devil? Is it likely to


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Cell_Biology_Alberts. Moreover, one of the Tasmanian devils has an inversion on chromosome 5 that is not present in its facial tumor. How do you suppose this cancer is transmitted from devil to devil? Is it likely to arise as a consequence of an infection by a virus or microorganism? Explain your reasoning.


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Cell_Biology_Alberts. Figure Q20–3 Karyotypes of cells from Tasmanian devils (Problem 20–11). (A) A Tasmanian devil. (B) Normal karyotype for a male Tasmanian devil. The karyotype has 14 chromosomes, including XY. (C) Karyotype of cancer cells found in each of the 11 facial tumors studied. The karyotype has 13 chromosomes, no sex chromosomes, no chromosome 2 pair, one chromosome 6, two chromosomes 1 with deleted long arms, and four highly rearranged marker chromosomes (M1–M4). (A, reproduced courtesy of Museum Victoria; B and C, from A.M. Pearse and K. Swift, Nature 439:549, 2006. With permission from Macmillan Publishers Ltd.) Bishop JM (2004) how to Win the Nobel Prize: An Unexpected Life in Science. Cambridge, MA: harvard University Press. hanahan D & Weinberg RA (2011) hallmarks of cancer: the next generation. Cell 144, 646–674. Vogelstein B, Papadopoulos N, Velculescu VE et al. (2013) Cancer genome landscapes. Science 339, 1546–1558.


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Cell_Biology_Alberts. Vogelstein B, Papadopoulos N, Velculescu VE et al. (2013) Cancer genome landscapes. Science 339, 1546–1558. Weinberg RA (2013) The Biology of Cancer, 2nd ed. Garland Science: New York. Cancer as a Microevolutionary Process Brown JM & Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat. Rev. Cancer 5, 231–237. Chambers AF, Naumov GN, Vantyghem S & Tuck AB (2000) Molecular biology of breast cancer metastasis. Clinical implications of experimental studies on metastatic inefficiency. Breast Cancer Res. 2, 400–407. Chi P, Allis CD & Wang GG (2010) Covalent histone modifications— miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10, 457–469. Fidler IJ (2003) The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat. Rev. Cancer 3, 453–458. hoeijmakers JhJ (2001) Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374.


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Cell_Biology_Alberts. hoeijmakers JhJ (2001) Genome maintenance mechanisms for preventing cancer. Nature 411, 366–374. Joyce JA & Pollard JW (2009) Microenvironmental regulation of metastasis. Nat. Rev. Cancer 9, 239–252. Lowe SW, Cepero E & Evan G (2004) Intrinsic tumour suppression. Nature 432, 307–315. Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194, 23–28. Stephens PJ, McBride DJ, Lin M-L et al. (2009) Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010. Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer 2, 442–454. Vander heiden MG, Cantley LC & Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033. Zink D, Fischer Ah & Nickerson JA (2004) Nuclear structure in cancer cells. Nat. Rev. Cancer 4, 677–687. Cancer-Critical Genes: How They Are Found and What They Do


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Cell_Biology_Alberts. Zink D, Fischer Ah & Nickerson JA (2004) Nuclear structure in cancer cells. Nat. Rev. Cancer 4, 677–687. Cancer-Critical Genes: How They Are Found and What They Do Berdasco M & Esteller M (2010) Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev. Cell 19, 698–711. Brognard J & hunter T (2011) Protein kinase signaling networks in cancer. Curr. Opin. Genet. Dev. 21, 4–11. Eilers M & Eisenman R (2008) Myc’s broad reach. Genes Dev. 22, 2755–2766. Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440. Garraway LA & Lander ES (2013) Lessons from the cancer genome. Cell 153, 17–37. Greaves M & Maley CC (2012) Clonal evolution in cancer. Nature 481, 306–313. Junttila MR & Evan GI (2009) p53—a Jack of all trades but master of none. Nat. Rev. Cancer 9, 821–829.


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Cell_Biology_Alberts. Greaves M & Maley CC (2012) Clonal evolution in cancer. Nature 481, 306–313. Junttila MR & Evan GI (2009) p53—a Jack of all trades but master of none. Nat. Rev. Cancer 9, 821–829. Levine AJ (2009) The common mechanisms of transformation by the small DNA tumor viruses: the inactivation of tumor suppressor gene products: p53. Virology 384, 285–293. Lu P, Weaver VM & Werb Z (2012) The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196, 395–406. Mitelman F, Johansson B & Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233–245. Negrini S, Gorgoulis VG & halazonetis TD (2010) Genomic instability— an evolving hallmark of cancer. Nat. Rev. Mol. Cell Biol. 11, 220–228. Nguyen DX, Bos PD & Massagué J (2009) Metastasis: from dissemination to organ-specific colonization. Nat. Rev. Cancer 9, 274–284. Radtke F & Clevers h (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307, 1904–1909.


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Cell_Biology_Alberts. Radtke F & Clevers h (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307, 1904–1909. Rowley JD (2001) Chromosome translocations: dangerous liaisons revisited. Nat. Rev. Cancer 1, 245–250. Shaw RJ & Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441, 424–430. Suvà ML, Riggi N & Bernstein BE (2013) Epigenetic reprogramming in cancer. Science 339, 1567–1570. Weinberg RA (1995) The retinoblastoma protein and cell cycle control. Cell 81, 323–330. Cancer Prevention and Treatment: Present and Future Al-hajj M, Becker MW, Wicha M et al. (2004) Therapeutic implications of cancer stem cells. Curr. Opin. Genet. Dev. 14, 43–47. Ames B, Durston WE, Yamasaki E & Lee FD (1973) Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc. Natl Acad. Sci. USA 70, 2281–2285.


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Cell_Biology_Alberts. Bozic I, Reiter JG, Allen B et al. (2013) Evolutionary dynamics of cancer in response to targeted combination therapy. eLife 2, e00747. Doll R & Peto R (1981) The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J. Natl Cancer Inst. 66, 1191–1308. Druker BJ & Lydon NB (2000) Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia. J. Clin. Invest. 105, 3–7. huang P & Oliff A (2001) Signaling pathways in apoptosis as potential targets for cancer therapy. Trends Cell Biol. 11, 343–348. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62. Jonkers J & Berns A (2004) Oncogene addiction: sometimes a temporary slavery. Cancer Cell 6, 535–538. Kalos M & June Ch (2013) Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39, 49–60.


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Cell_Biology_Alberts. Kalos M & June Ch (2013) Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39, 49–60. Loeb LA (2011) human cancers express mutator phenotypes: origin, consequences and targeting. Nat. Rev. Cancer 11, 450–457. Lord CJ & Ashworth A (2012) The DNA damage response and cancer therapy. Nature 481, 287–294. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264. Peto J (2001) Cancer epidemiology in the last century and the next decade. Nature 411, 390–395. Sawyers C (2004) Targeted cancer therapy. Nature 432, 294–297. Schreiber RD, Old LJ & Smyth MJ (2011) Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570. Sliwkowski MX & Mellman I (2013) Antibody therapeutics in cancer. Science 341, 1192–1198. Varmus h, Pao W, Politi K et al. (2005) Oncogenes come of age. Cold Spring Harb. Symp. Quant. Biol. 70, 1–9.


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Cell_Biology_Alberts. Varmus h, Pao W, Politi K et al. (2005) Oncogenes come of age. Cold Spring Harb. Symp. Quant. Biol. 70, 1–9. Ward RJ & Dirks PB (2007) Cancer stem cells: at the headwaters of tumor development. Annu. Rev. Pathol. 2, 175–189. Development of Multicellular Organisms 21 An animal or plant starts its life as a single cell—a fertilized egg, or zygote. During development, this cell divides repeatedly to produce many different kinds of cells, arranged in a final pattern of spectacular complexity and precision. The goal of developmental cell biology is to understand the cellular and molecular mechanisms that direct this amazing transformation (Movie 21.1).


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Cell_Biology_Alberts. Plants and animals have very different ways of life, and they use different developmental strategies; in this chapter, we focus mainly on animals. Four processes are fundamental to animal development: (1) cell proliferation, which produces many cells from one; (2) cell–cell interactions, which coordinate the behavior of each cell with that of its neighbors; (3) cell specialization, or differentiation, which creates cells with different characteristics at different positions; and (4) cell movement, which rearranges the cells to form structured tissues and organs (Figure 21–1). It is on the fourth point that plant development differs radically: plant cells are unable to migrate or move independently through the embryo because each one is contained within a cell wall, through which it is cemented to its neighbors, as discussed in Chapter 19.


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Cell_Biology_Alberts. In a developing animal embryo, the four fundamental processes are happening in a kaleidoscopic variety of ways, as they give rise to different parts of the organism. Like the members of an orchestra, the cells in the embryo have to play their individual parts in a highly coordinated manner. In the embryo, however, there is no conductor—no central authority—to direct the performance. Instead, development is a self-assembly process in which the cells, as they grow and proliferate, organize themselves into increasingly complex structures. Each of the millions of cells has to choose for itself how to behave, selectively utilizing the genetic instructions in its chromosomes.


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Cell_Biology_Alberts. At each stage in its development, the cell is presented with a limited set of options, so that its developmental pathway branches repeatedly, reflecting a large set of sequential choices. Like the decisions we make in our own lives, the choices made by the cell are based on its internal state—which largely reflects its history—and on current influences from other cells, especially its close neighbors. To understand development, we need to know how each choice is controlled and how it depends on previous choices. Beyond that, we need to understand how the choices, once made, influence the cell’s chemistry and behavior, and how cell behaviors act synergistically to determine the structure and function of the body. Figure 21–1 The four essential cell processes that allow a multicellular organism to be made.


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Cell_Biology_Alberts. Figure 21–1 The four essential cell processes that allow a multicellular organism to be made. As cells become specialized they change not only their chemistry but also their shape and their attachments to other cells and to the extracellular matrix. They move and rearrange themselves to create the complex architecture of the body, with all its tissues and organs, each structured precisely and defined in size. To understand this process of form generation, or morphogenesis, we will need to take account of the mechanical, as well as the biochemical, interactions between the cells.


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Cell_Biology_Alberts. At first glance, one would no more expect the worm, the flea, the eagle, and the giant squid all to be generated by the same developmental mechanisms than one would suppose that the same methods were used to make a shoe and an airplane. Remarkably, however, research in the past 30 years has revealed that much of the basic machinery of development is essentially the same in all animals—not just in all vertebrates, but in all the major phyla of invertebrates too. Recognizably similar, evolutionarily related molecules define the specialized animal cell types, mark the differences between body regions, and help create the animal body pattern. Homologous proteins are often functionally interchangeable between very different species. Thus, a human protein produced artificially in a fly, for example, can perform the same function as the fly’s own version of that protein (Figure 21–2). Thanks to an underlying unity of mechanisms, developmental biologists have been making great strides toward


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Cell_Biology_Alberts. can perform the same function as the fly’s own version of that protein (Figure 21–2). Thanks to an underlying unity of mechanisms, developmental biologists have been making great strides toward a coherent understanding of animal development.


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Cell_Biology_Alberts. We begin this chapter with an overview of some of the basic mechanisms that operate in animal development. We then discuss, in sequence, how cells in the embryo diversify to form patterns in space, how the timing of developmental events is controlled, how cell movements contribute to morphogenesis, and how the size of an animal is regulated. We end by considering the most challenging aspect of development—the mechanisms that enable a highly complex nervous system to form. misexpression of Eyeless/Pax6 in misexpression of wild type wing precursors Eyeless/Pax6 in leg precursors


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Cell_Biology_Alberts. misexpression of Eyeless/Pax6 in misexpression of wild type wing precursors Eyeless/Pax6 in leg precursors Figure 21–2 Homologous proteins can function interchangeably. (a–c) the eyeless protein (also called pax6) controls eye development in Drosophila and, when misexpressed during development, can cause an eye to form in an abnormal site, such as a wing (B) or a leg (c). the scanning electron micrographs show a patch of eye tissue on the leg of a fly resulting from misexpression of Drosophila Eyeless (e) and of squid Pax6 (F). the homologous protein from a human or practically any animal possessing eyes, when similarly misexpressed in a transgenic fly, has the same effect. the entire eye of a normal Drosophila is shown for comparison in (a) and (D). (B–c, courtesy of Georg halder; D–F, from S. I. tomarev, et al. Proc. Natl Acad. Sci. USA 94:2421–2426, 1997. With permission from National academy of Sciences.)


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Cell_Biology_Alberts. Animals live by eating other organisms. Thus, despite their remarkable diversity, animals as different as worms, mollusks, insects, and vertebrates share anatomical features that are fundamental to this way of life. Epidermal cells form a protective outer layer; gut cells absorb nutrients from ingested food; muscle cells allow movement; and neurons and sensory cells control behavior. These diverse cell types are organized into tissues and organs, forming a sheet of skin covering the exterior, a mouth for feeding, and an internal gut tube to digest food—with muscles, nerves, and other tissues arranged in the space between the skin and the gut tube. Many animals have clearly defined axes—an anteroposterior axis, with mouth and brain anterior and anus posterior; a dorsoventral axis, with back dorsal and belly ventral; and a left-right axis. In this section, we discuss some fundamental mechanisms underlying animal development, beginning with how the basic animal body plan is established.


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Cell_Biology_Alberts. conserved Mechanisms establish the Basic animal Body plan


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Cell_Biology_Alberts. The shared anatomical features of animals develop through conserved mechanisms. After fertilization, the zygote usually divides rapidly, or cleaves, to form many smaller cells; during this cleavage, the embryo, which cannot yet feed, does not grow. This phase of development is initially driven and controlled entirely by the material deposited in the egg by the mother. The embryonic genome remains inactive until a point is reached when maternal mRNAs and proteins rather abruptly begin to be degraded. The embryo’s genome is activated, and the cells cohere to form a blastula—typically a solid or a hollow fluid-filled ball of cells. Complex cell rearrangements called gastrulation (from the Greek “gaster,” meaning “belly”) then transform the blastula into a multilayered structure containing a rudimentary internal gut (Figure 21–3). Some cells of the blastula remain external, constituting the ectoderm, which will give rise to the epidermis and the nervous system; other cells invaginate,


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Cell_Biology_Alberts. a rudimentary internal gut (Figure 21–3). Some cells of the blastula remain external, constituting the ectoderm, which will give rise to the epidermis and the nervous system; other cells invaginate, forming the endoderm, which will give rise to the gut tube and its appendages, such as lung, pancreas, and liver. Another group of cells moves into the space between ectoderm and endoderm and forms the mesoderm, which will give rise to muscles, connective tissues, blood, kidney, and various other components. Further cell movements and accompanying cell differentiations create and refine the embryo’s architecture.


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Cell_Biology_Alberts. Figure 21–3 The early stages of development, as exemplified by a frog.


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Cell_Biology_Alberts. (a) a fertilized egg divides to produce a blastula—a sheet of epithelial cells often surrounding a cavity. During gastrulation, some of the cells tuck into the interior to form the mesoderm (green) and endoderm (yellow). ectodermal cells (blue) remain on the outside. (B) a cross section through the trunk of an amphibian embryo shows the basic animal body plan, with a sheet of ectoderm on the outside, a tube of endoderm on the inside, and mesoderm sandwiched between them. the endoderm forms the epithelial lining of the gut, from the mouth to the anus. It gives rise not only to the pharynx, esophagus, stomach, and intestines, but also to many associated structures. the salivary glands, liver, pancreas, trachea, and lungs, for example, all develop from the wall of the digestive tract and grow to become systems of branching tubes that open into the gut or pharynx. the endoderm forms only the epithelial components of these structures— the lining of the gut and the secretory cells of the


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Cell_Biology_Alberts. to become systems of branching tubes that open into the gut or pharynx. the endoderm forms only the epithelial components of these structures— the lining of the gut and the secretory cells of the pancreas, for example. the supporting muscular and fibrous elements arise from the mesoderm.


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Cell_Biology_Alberts. the mesoderm gives rise to the connective tissues—at first, to the loose mesh of cells in the embryo known as mesenchyme, and ultimately to cartilage, bone, and fibrous tissue, including the dermis (the inner layer of the skin). the mesoderm also forms the muscles, the entire vascular system—including the heart, blood vessels, and blood cells—and the tubules, ducts, and supporting tissues of the kidneys and gonads. the notochord forms from the mesoderm and serves as the core of the future backbone and the source of signals that coordinate the development of surrounding tissues.


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Cell_Biology_Alberts. the ectoderm will form the epidermis (the outer, epithelial layer of the skin) and epidermal appendages such as hair, sweat glands, and mammary glands. It will also give rise to the whole of the nervous system, central and peripheral, including not only neurons and glia but also the sensory cells of the nose, the ear, the eye, and other sense organs. (B, after t. Mohun et al., Cell 22:9–15, 1980. With permission from elsevier.) The ectoderm, mesoderm, and endoderm formed during gastrulation constitute the three germ layers of the early embryo. Many later developmental transformations will produce the elaborately structured organs. But the basic body plan and axes set up in miniature during gastrulation are preserved into adult life, when the organism may be billions of times larger (Movie 21.2). the Developmental potential of cells Becomes progressively restricted


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Cell_Biology_Alberts. Concomitant with the refinement of the body plan, the individual cells become more and more restricted in their developmental potential. During the blastula stages, cells are often totipotent or pluripotent—they have the potential to give rise to all or almost all of the cell types of the adult body. The pluripotency is lost as gastrulation proceeds: a cell located in the endodermal germ layer, for example, can give rise to the cell types that will line the gut or form gut-derived organs such as the liver or pancreas, but it no longer has the potential to form mesoderm-derived structures such as skeleton, heart, or kidney. Such a cell is said to be determined for an endodermal fate. Thus, cell determination starts early and progressively narrows the options as the cell steps through a programmed series of intermediate states—guided at each step by its genome, its history, and its interactions with neighbors. The process reaches its limit when a cell undergoes terminal differentiation


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Cell_Biology_Alberts. series of intermediate states—guided at each step by its genome, its history, and its interactions with neighbors. The process reaches its limit when a cell undergoes terminal differentiation to form one of the highly specialized cell types of the adult body (Figure 21–4). Although there are cell types in the adult that retain some degree of pluripotency, their range of options is generally narrow (discussed in Chapter 22).


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Cell_Biology_Alberts. Underlying the richness and astonishingly complex outcomes of development is cell memory (see p. 404). Both the genes a cell expresses and the way it behaves depend on the cell’s past, as well as on its present circumstances. The cells of our body—the muscle cells, the neurons, the skin cells, the gut cells, and so on—maintain their specialized characters largely because they retain a record of the extracellular signals their ancestors received during development, rather than because they continually receive such instructions from their surroundings. Despite their radically different phenotypes, they retain the same complete genome that was present in the zygote; their differences arise instead from differential gene expression. We have discussed the molecular mechanisms of gene regulation, cell memory, cell division, cell signaling, and cell movement in previous chapters. In this chapter, we shall see how these basic processes are collectively deployed to create an animal.


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Cell_Biology_Alberts. The anatomical features that animals share have undergone many extreme modifications in the course of evolution. As a result, the differences between species are usually more striking to our human eye than the similarities. But at the level of the underlying molecular mechanisms and the macromolecules that mediate them, the reverse is true: the similarities among all animals are profound and extensive. Through more than half a billion years of evolutionary divergence, all animals have retained unmistakably similar sets of genes and proteins that are responsible for generating their body plans and for forming their specialized cells and organs.


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Cell_Biology_Alberts. This astonishing degree of evolutionary conservation was discovered not by broad surveys of animal diversity, but through intensive study of a small number of representative species—the model organisms discussed in Chapter 1. For animal developmental biology, the most important have been the fly Drosophila melanogaster, the frog Xenopus laevis, the roundworm Caenorhabditis elegans, the mouse Mus musculus, and the zebrafish Danio rerio. In discussing the mechanisms of development, we shall draw our examples mainly from these few species. Figure 21–4 The lineage from blastomere to differentiated cell type. as development proceeds, cells become more and more specialized. Blastomeres have the potential to give rise to most or all cell types. Under the influence of signaling molecules and gene regulatory factors, cells acquire more restricted fates until they differentiate into highly specialized cell types, such as the pancreatic β-islet cells that secrete the hormone insulin.


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Cell_Biology_Alberts. Genes Involved in cell–cell communication and transcriptional control are especially Important for animal Development


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Cell_Biology_Alberts. What are the genes that animals share with one another but not with other kingdoms of life? These would be expected to include genes required specifically for animal development but not needed for unicellular existence. Comparison of animal genomes with the genome of budding yeast—a unicellular eukaryote— suggests that three classes of genes are especially important for multicellular organization. The first class includes genes that encode proteins used for cell–cell adhesion and cell signaling; hundreds of human genes encode signal proteins, cell-surface receptors, cell adhesion proteins, or ion channels that are either not present in yeast or present in much smaller numbers. The second class includes genes encoding proteins that regulate transcription and chromatin structure: more than 1000 human genes encode transcription regulators, but only about 250 yeast genes do so. As we shall see, the development of animals is dominated by cell–cell interactions and by differential gene


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Cell_Biology_Alberts. 1000 human genes encode transcription regulators, but only about 250 yeast genes do so. As we shall see, the development of animals is dominated by cell–cell interactions and by differential gene expression. The third class of non-coding RNAs has a more uncertain status: it includes genes that encode microR-NAs (miRNAs); there are at least 500 of these in humans. Along with the regulatory proteins, they play a significant part in controlling gene expression during animal development, but the full extent of their importance is still unclear. The loss of individual miRNA genes in C. elegans, where their functions have been well studied, rarely leads to obvious phenotypes, suggesting that the roles of miRNAs during animal development are often subtle, serving to fine-tune the developmental machinery rather than to form its core structures.


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Cell_Biology_Alberts. regulatory DNa Seems Largely responsible for the Differences Between animal Species As discussed in Chapter 7, each gene in a multicellular organism is associated with many thousands of nucleotides of noncoding DNA that contains regulatory elements. These regulatory elements determine when, where, and how strongly the gene is to be expressed, according to the transcription regulators and chromatin structures that are present in the particular cell (Figure 21–5). Consequently, a change in the regulatory DNA, even without any change in the coding DNA, can alter the logic of the gene-regulatory network and change the outcome of development.


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Cell_Biology_Alberts. As discussed in Chapter 4, when we compare the genomes of different animal species, we find that evolution has altered the coding and regulatory DNA to different extents. The coding DNA, for the most part, has been highly conserved, the noncoding regulatory DNA much less so. It seems that changes in regulatory DNA are largely responsible for the dramatic differences between one class of animals and another (see p. 227). We can view the protein products of the coding sequences as a conserved kit of common molecular parts, and the regulatory DNA as instructions for assembly: with different instructions, the same kit of parts can be used to make a whole variety of different body structures. We will return to this important concept later.


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Cell_Biology_Alberts. Figure 21–5 Regulatory DNA defines the gene expression patterns in development. the genome is the same in a muscle cell as in a skin cell, but different genes are active because these cells express different transcription regulators that bind to gene regulatory elements. For example, transcription regulators in skin cells recognize a regulatory element in gene 1, leading to its activation, whereas a different set of regulators is present in muscle cells, binding to and activating gene 3. transcriptional regulators that activate the expression of gene 2 are present in both cell types. Small Numbers of conserved cell–cell Signaling pathways coordinate Spatial patterning


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Cell_Biology_Alberts. Spatial patterning of a developing animal requires that cells become different according to their positions in the embryo, which means that cells must respond to extracellular signals produced by other cells, especially their neighbors. In what is probably the commonest mode of spatial patterning, a group of cells starts out with the same developmental potential, and a signal from cells outside the group then induces one or more members of the group to change their character. This process is called inductive signaling. Generally, the inductive signal is limited in time and space so that only a subset of the cells capable of responding—the cells close to the source of the signal—take on the induced character (Figure 21–6). Some inductive signals depend on cell–cell contact; others act over a longer range and are mediated by molecules that diffuse through the extracellular medium or are transported in the bloodstream (see Figure 15–2).


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Cell_Biology_Alberts. Most of the known inductive events in animal development are governed by a small number of highly conserved signaling pathways, including transforming growth factor-β (TGFβ), Wnt, Hedgehog, Notch, and receptor tyrosine kinase (RTK) pathways (discussed in Chapter 15). The discovery of the limited vocabulary that developing cells use for intercellular communication has emerged over the past 25 years as one of the great simplifying features of developmental biology. through combinatorial control and cell Memory, Simple Signals can Generate complex patterns


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Cell_Biology_Alberts. But how can this small number of signaling pathways generate the huge diversity of cells and patterns? Three kinds of mechanisms are responsible. First, through gene duplication, the basic components of a pathway often come to be encoded by small families of closely related homologous genes. This allows for diversity in the operation of the pathway, according to which family member is employed in a given situation. Notch signaling, for example, may be mediated by Notch1 in one tissue, but by its homolog Notch4 in another. Second, the response of a cell to a given signal protein depends on the other signals that the cell is receiving concurrently (Figure 21–7A). As a result, different combinations of signals can generate a large variety of different responses. Third, and most fundamental, the effect of activating a signaling pathway depends on the previous experiences of the responding cell: past influences leave a lasting mark, registered in the state of the cell’s chromatin and the


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Cell_Biology_Alberts. the effect of activating a signaling pathway depends on the previous experiences of the responding cell: past influences leave a lasting mark, registered in the state of the cell’s chromatin and the selection of transcription regulatory proteins and RNA molecules that the cell contains. This cell memory enables cells with different cells directed to new developmental pathway


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Cell_Biology_Alberts. Figure 21–6 Inductive signaling. Figure 21–7 Two mechanisms for generating different responses to the same inductive signal. (a) In combinatorial signaling, the effect of a signal depends on the presence of other signals received at the same time. (B) through cell memory, previous signals (or other events) can leave a lasting trace that alters the response to the current signal (see Figure 7–54). the memory trace is represented here in the coloring of the cell nucleus. feld of cells morphogen gradient forms source of morphogen cellular response to gradient 0.1 mm histories to respond to the same signals differently (Figure 21–7B). Thus, the same few signaling pathways can be used repeatedly at different times and places with different outcomes, so as to generate patterns of unlimited complexity. Morphogens are Long-range Inductive Signals that exert Graded effects


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Cell_Biology_Alberts. Morphogens are Long-range Inductive Signals that exert Graded effects Signal molecules often govern simple yes–no choices—one outcome when their concentration is high, another when it is low. In many cases, however, the responses are more finely graded: a high concentration of a signal molecule may, for example, direct cells into one developmental pathway, an intermediate concentration into another, and a low concentration into yet another.


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Cell_Biology_Alberts. One common way to generate such different concentrations of a signal molecule is for the molecule to diffuse out from a localized signaling source, creating a concentration gradient. Cells at different distances from the source are driven to behave in a variety of different ways, according to the signal concentration that they experience (Figure 21–8). A signal molecule that imposes a pattern on a whole field of cells in this way is called a morphogen. In the simplest case, a specialized group of cells produces a morphogen at a steady rate, and the morphogen is then degraded as it diffuses away from this source. The speed of diffusion and the half-life of the morphogen will together determine the range and steepness of its resulting gradient (Figure 21–9).


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Cell_Biology_Alberts. This simple mechanism can be modified in various ways. Receptors on the surface of cells along the way, for example, may trap the diffusing morphogen and cause it to be endocytosed and degraded, shortening its effective half-life. Alternatively, the morphogen may bind to molecules in the extracellular matrix such as heparan sulfate proteoglycan (discussed in Chapter 19), thereby greatly reducing its diffusion rate. Lateral Inhibition can Generate patterns of Different cell types Morphogen gradients, and other kinds of inductive signal, exploit an existing asymmetry in the embryo to create further asymmetries and differences between cells: already, at the outset, some cells are specialized to produce the morphogen and thereby impose a pattern on another class of cells that are sensitive to it. But 0 0.1 0.2 0 0.1 0.2 0 0.1 0.2 distance from source (mm)


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Cell_Biology_Alberts. Figure 21–8 Gradient formation and interpretation. a gradient forms by localized production of an inducer—a morphogen—that diffuses away from its source. Different concentrations of morphogen (or different durations of exposure) induce different gene expression patterns and cell fates in responding cells. Diffusive transport can generate gradients only over short distances, and morphogens generally act over distances of 1 mm or less.


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Cell_Biology_Alberts. Figure 21–9 Setting up a signal gradient by diffusion. (a–c) each graph shows six successive stages in the buildup of the concentration of a signal molecule that is produced at a steady rate at the origin, with production starting at time 0. In all cases, the molecule undergoes degradation as it diffuses away from the source, and the graphs are calculated on the assumption that diffusion is occurring along two axes in space (for example, radially from a source in an epithelial sheet). (a) the pattern of the morphogen assuming that the molecule has a half-life of 170 minutes, and that it diffuses with an effective diffusion constant of D = 1 μm2 sec–1, typical of a small protein molecule in extracellular tissues. Note that the gradient is already close to its steady-state form within an hour and that the concentration at steady state falls off exponentially with distance. (B) a threefold increase in the diffusion constant of the morphogen extends its range but lowers its concentration


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Cell_Biology_Alberts. and that the concentration at steady state falls off exponentially with distance. (B) a threefold increase in the diffusion constant of the morphogen extends its range but lowers its concentration next to the source, whereas (c) a threefold increase in morphogen half-life increases its concentration throughout the tissue. effects of the morphogen will depend not just on its concentration at some critical moment, but also on how each target cell integrates its response over time. (courtesy of patrick Müller.)


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Cell_Biology_Alberts. Figure 21–10 Genesis of asymmetry through lateral inhibition and positive feedback. In this example, two cells interact, each producing a substance X that acts on the other cell to inhibit its production of X, an effect known as lateral inhibition. an increase of X in one of the cells leads to a positive feedback that tends to increase X in that cell still further, while decreasing X in its neighbor. this can create a runaway instability, making the two cells become radically different. Ultimately, the system comes to rest in one or the other of two opposite stable states. the final choice of state represents a form of memory: the small influence that initially directed the choice is no longer required to maintain it. what if there is no clear initial asymmetry? Can a regular pattern arise spontaneously within a set of cells that are initially all alike?


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Cell_Biology_Alberts. what if there is no clear initial asymmetry? Can a regular pattern arise spontaneously within a set of cells that are initially all alike? The answer is yes. The fundamental principle underlying such de novo pattern formation is positive feedback: cells can exchange signals in such a way that any small initial discrepancy between cells at different sites becomes self-amplifying, driving the cells toward different fates. This is most clearly illustrated in the phenomenon of lateral inhibition, a form of cell–cell interaction that forces close neighbors to become different and thereby generates fine-grained patterns of different cell types.


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Cell_Biology_Alberts. Consider a pair of adjacent cells that start off in a similar state. Each of these cells can both produce and respond to a certain signal molecule X, with the added rule that the stronger the signal a cell receives, the weaker the signal it generates (Figure 21–10). If one cell produces more X, the other is forced to produce less. This gives rise to a positive feedback loop that tends to amplify any initial difference between the two adjacent cells. Such a difference may arise from a bias imposed by some present or past external factor, or it may simply originate from spontaneous random fluctuations, or “noise”—an inevitable feature of the genetic control circuitry in cells (discussed in Chapter 7). In either case, lateral inhibition means that if cell 1 makes a little more of X, it will thereby cause cell 2 to make less; and because cell 2 makes less X, it delivers less inhibition to cell 1 and so allows the production of X in cell 1 to rise higher still; and so on, until a steady


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Cell_Biology_Alberts. thereby cause cell 2 to make less; and because cell 2 makes less X, it delivers less inhibition to cell 1 and so allows the production of X in cell 1 to rise higher still; and so on, until a steady state is reached where cell 1 produces a lot of X and cell 2 produces very little. In the standard case, the signal molecule X acts in the receiving cell by regulating gene transcription, and the result is that the two cells are driven along different pathways of differentiation.


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Cell_Biology_Alberts. In almost all tissues, a balanced mixture of different cell types is required. Lateral inhibition provides a common way to generate the mixture. As we shall see, lateral inhibition is very often mediated by exchange of signals at cell– cell contacts via the Notch signaling pathway, driving cell diversification by enabling individual cells that express one set of genes to direct their immediate neighbors to express a different set, in exactly the way we have described (see also Figure 15–58).


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Cell_Biology_Alberts. Lateral inhibition mediated by the Notch pathway is not the only example of pattern generation through positive feedback: there are other ways in which, through the same basic principle, a system that starts off homogeneous and symmetrical can pattern itself spontaneously, even in the absence of an external morphogen. Positive feedback processes mediated by diffusible signal molecules can operate over broad arrays of cells to create many types of spatial patterns. Mechanisms of this sort are called reaction-diffusion systems. For example, a substance A (a short-range activator) may stimulate its own production in the cells that contain it and in their immediate neighbors, while also causing these cells to produce a signal I (a long-range inhibitor) that diffuses widely and inhibits the production of A in cells farther away. If the cells all start the same, but one group gains a slight advantage by making a little more A than the rest, the asymmetry can be self-amplifying


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Cell_Biology_Alberts. POSITIVE FEEDBACK: asymmetry is self-amplifying Figure 21–11 Pattern generation by a reaction-diffusion system. From (a) a uniform field of cells, (B) local positive feedback and (c) long-range inhibition can (D) generate patterns within the initially uniform field. the patterns can be complex, resembling the spots of a leopard (as shown) or the stripes of a zebra; or they can be simple, with creation of a single cluster of specialized cells that can, for example, go on to serve as the source of a morphogen gradient. (Figure 21–11). Such short-range activation combined with long-range inhibition can account for the formation of clusters of cells within an initially homogeneous tissue that become specialized as localized signaling centers.


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Cell_Biology_Alberts. Cell diversification does not always depend on extracellular signals: in some cases, daughter cells are born different as a result of an asymmetric cell division, in which some important molecule or molecules are distributed unequally between the two daughters. This asymmetric inheritance ensures that the two daughter cells develop differently (Figure 21–12). Asymmetric division is a common feature of early development, where the fertilized egg already has an internal pattern and cleavage of this large cell segregates different determinants into separate blastomeres. We shall see that asymmetric division also plays a part in some later developmental processes. Initial patterns are established in Small Fields of cells and refined by Sequential Induction as the embryo Grows


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Cell_Biology_Alberts. Initial patterns are established in Small Fields of cells and refined by Sequential Induction as the embryo Grows The signals that organize the spatial pattern of cells in an embryo generally act over short distances and govern relatively simple choices. A morphogen, for example, typically acts over a distance of less than 1 mm—an effective range for diffusion —and directs choices between several developmental options for the cells on which it acts. Yet the organs that eventually develop are much larger and more complex than this.