ART TK Cancer and the chapter 22 Immune system S THE DEATH TOLL FROM INFECTIOUS DISEASE has declined in the Western world, cancer has become the second-ranking cause of death there. led only by heart disease. Current estimates project that one person in three in the United States will develop cancer, that one in five will die from it. From an immunologic per spective, cancer cells can be viewed as altered self-cells that have escaped normal growth-regulating mechanisms. This chapter examines the unique properties of cancer cells, pay. ing particular attention to those properties that can be recog- Cancerous melanoma cells nized by the immune system. The immune responses that develop to cancer cells, as well as the methods by which can cers manage to evade those responses, are then described. Cancer: Origin and Terminolo The final section describes current clinical and experimental a Malignant Transformation of Cells unotherapies for cancer. Oncogenes and Cancer Induction a Tumors of the Immune System Cancer: Origin and Terminology s Tumor Antigens In most organs and tissues of a mature animal, a balance is Immune Response to Tumors usually maintained between cell renewal and cell death. The Tumor Evasion of the Immune System various types of mature cells in the body have a given life span: as these cells die, new cells are generated by the prolif- Cancer Immunotherapy eration and differentiation of various types of stem cells. Under normal circumstances, the production of new cells is regulated so that the number of any particular type of cell constant. Occasionally, though, cells arise that longer respond to normal growth-control mechanisms. These cells give rise to clones of cells that can expand to a consider- of cancers of the colon, breast, prostate, and lung are carci- able size, producing a tumor, or neoplasm. nomas. The leukemias and lymphomas are malignant tu- A tumor that is not capable of indefinite growth and does mors of hematopoietic cells of the bone marrow and ac- not invade the healthy surrounding tissue extensively is be- count for about 9% of cancer incidence in the United States nign. a tumor that continues to grow and becomes progres- Leukemias proliferate as single cells, whereas lymphomas sively invasive is malignant; the term cancer refers speci- tend to grow as tumor masses. Sarcomas, which arise less fically to a malignant tumor. In addition to uncontrolled frequently (around 1% of the incidence in the United States) growth, malignant tumors exhibit metastasis; in this pro- are derived from mesodermal connective tissues such as ess, small clusters of cancerous cells dislodge from a tumor, bone, fat, and cartilage evade the blood or lymphatic vessels, and are carried to other tissues, where they continue to proliferate. In this way a primary tumor at one site can give rise to a secondary Malignant Transformation of Cells Malignant tumors or cancers are classified according to Treatment of normal cultured cells with chemical carcino- he embryonic origin of the tissue from which the tumor is gens, irradiation, and certain viruses can alter their mor derived. Most(>80%)are carcinomas, tumors that arise phology and growth properties. In some cases this process from endodermal or ectodermal tissues such as skin or the referred to as transformation, makes the cells able to pro- epithelial lining of internal organs and glands. The majority duce tumors when they are injected into animals. Such cells
■ Cancer: Origin and Terminology ■ Malignant Transformation of Cells ■ Oncogenes and Cancer Induction ■ Tumors of the Immune System ■ Tumor Antigens ■ Immune Response to Tumors ■ Tumor Evasion of the Immune System ■ Cancer Immunotherapy Cancerous melanoma cells. Cancer and the Immune System A has declined in the Western world, cancer has become the second-ranking cause of death there, led only by heart disease. Current estimates project that one person in three in the United States will develop cancer, and that one in five will die from it. From an immunologic perspective, cancer cells can be viewed as altered self-cells that have escaped normal growth-regulating mechanisms. This chapter examines the unique properties of cancer cells, paying particular attention to those properties that can be recognized by the immune system. The immune responses that develop to cancer cells, as well as the methods by which cancers manage to evade those responses, are then described. The final section describes current clinical and experimental immunotherapies for cancer. Cancer: Origin and Terminology In most organs and tissues of a mature animal, a balance is usually maintained between cell renewal and cell death. The various types of mature cells in the body have a given life span; as these cells die, new cells are generated by the proliferation and differentiation of various types of stem cells. Under normal circumstances, the production of new cells is regulated so that the number of any particular type of cell remains constant. Occasionally, though, cells arise that no longer respond to normal growth-control mechanisms. These cells give rise to clones of cells that can expand to a considerable size, producing a tumor, or neoplasm. A tumor that is not capable of indefinite growth and does not invade the healthy surrounding tissue extensively is benign. A tumor that continues to grow and becomes progressively invasive is malignant; the term cancer refers specifically to a malignant tumor. In addition to uncontrolled growth, malignant tumors exhibit metastasis; in this process, small clusters of cancerous cells dislodge from a tumor, invade the blood or lymphatic vessels, and are carried to other tissues, where they continue to proliferate. In this way a primary tumor at one site can give rise to a secondary tumor at another site (Figure 22-1). Malignant tumors or cancers are classified according to the embryonic origin of the tissue from which the tumor is derived. Most (>80%) are carcinomas, tumors that arise from endodermal or ectodermal tissues such as skin or the epithelial lining of internal organs and glands. The majority of cancers of the colon, breast, prostate, and lung are carcinomas. The leukemias and lymphomas are malignant tumors of hematopoietic cells of the bone marrow and account for about 9% of cancer incidence in the United States. Leukemias proliferate as single cells, whereas lymphomas tend to grow as tumor masses. Sarcomas, which arise less frequently (around 1% of the incidence in the United States), are derived from mesodermal connective tissues such as bone, fat, and cartilage. Malignant Transformation of Cells Treatment of normal cultured cells with chemical carcinogens, irradiation, and certain viruses can alter their morphology and growth properties. In some cases this process, referred to as transformation, makes the cells able to produce tumors when they are injected into animals. Such cells chapter 22 ART TK
502 RT Iv The Immune System in Health and Disease VISUALIZING CONCEPTS Initially modified tumor cell (b) Mass of tumor cells (localized benign Tumor cells metastasis to occur carried by the blood or lymph to other sites in the ign tumor. ( c) The tumor cells become progressively more inva- body /Adapted from 1 Amell et al., 1990, Molecular Cell Biology sive, invading the underlying basal lamina. The tumor is now 2d ed, Scientific American Books] are said to have undergone malignant transformation, and physical carcinogens appears to involve multiple steps and at they often exhibit properties in vitro similar to those of can- least two distinct phases: initiation and promotion. Initiation cer cells. For example, they have decreased requirements for involves changes in the genome but does not, in itself, lead to rowth factors and serum, are no longer anchorage-dependent, malignant transformation. After initiation, promoters stimu and grow in a density-independent fashion. Moreover, both late cell division and lead to malignant transformation. cancer cells and transformed cells can be subcultured indefi- The importance of mutagenesis in the induction of cancer nitely, that is, for all practical purposes, they are immortal. is illustrated by diseases such as xeroderma pigmentosum. Because of the similar properties of cancer and transformed This rare disorder is caused by a defect in the gene that en- cells, the process of malignant transformation has been stud- codes a DNA-repair enzyme called UV-specific endonuclease. ied extensively as a model of cancer induction. Individuals with this disease are unable to repair UV-induced Various chemical agents(e.g, DNA-alkylating reagents)and mutations and consequently develop skin cancers. physical agents (e.g, ultraviolet ight and ionizing radiation) A number of DNA and RNa viruses have been shown to that cause mutations have been shown to induce transforma- induce malignant transformation. Two of the best-studied tion. Induction of malignant transformation with chemical or are SV40 and polyoma. In both cases the viral genomes
are said to have undergone malignant transformation, and they often exhibit properties in vitro similar to those of cancer cells. For example, they have decreased requirements for growth factors and serum, are no longer anchorage-dependent, and grow in a density-independent fashion. Moreover, both cancer cells and transformed cells can be subcultured indefinitely; that is, for all practical purposes, they are immortal. Because of the similar properties of cancer and transformed cells, the process of malignant transformation has been studied extensively as a model of cancer induction. Various chemical agents (e.g., DNA-alkylating reagents) and physical agents (e.g., ultraviolet light and ionizing radiation) that cause mutations have been shown to induce transformation. Induction of malignant transformation with chemical or physical carcinogens appears to involve multiple steps and at least two distinct phases: initiation and promotion. Initiation involves changes in the genome but does not, in itself, lead to malignant transformation. After initiation, promoters stimulate cell division and lead to malignant transformation. The importance of mutagenesis in the induction of cancer is illustrated by diseases such as xeroderma pigmentosum. This rare disorder is caused by a defect in the gene that encodes a DNA-repair enzyme called UV-specific endonuclease. Individuals with this disease are unable to repair UV-induced mutations and consequently develop skin cancers. A number of DNA and RNA viruses have been shown to induce malignant transformation. Two of the best-studied are SV40 and polyoma. In both cases the viral genomes, 502 PART IV The Immune System in Health and Disease VISUALIZING CONCEPTS (a) (b) (c) (d) Initially modified tumor cell Invasive tumor cells Mass of tumor cells (localized benign tumor) Basal lamina Blood vessel Tumor cells invade blood vessels, allowing metastasis to occur FIGURE 22-1 Tumor growth and metastasis. (a) A single cell develops altered growth properties at a tissue site. (b) The altered cell proliferates, forming a mass of localized tumor cells, or benign tumor. (c) The tumor cells become progressively more invasive, invading the underlying basal lamina. The tumor is now classified as malignant. (d) The malignant tumor metastasizes by generating small clusters of cancer cells that dislodge from the tumor and are carried by the blood or lymph to other sites in the body. [Adapted from J. Darnell et al., 1990, Molecular Cell Biology, 2d ed., Scientific American Books.]
Cancer and the Immune System CHAPTER 22 503 which integrate randomly into the host chromosomal dna, gene and its corresponding proto-oncogene appear to have include several genes that are expressed early in the course of very similar functions. As described below, the conversion of viral replication. SV40 encodes two early proteins called large a proto-oncogene into an oncogene appears in many cases to Tand little T, and polyoma encodes three early proteins called accompany a change in the level of expression of a normal large T, middle T, and little T. Each of these proteins plays a growth-controlling protein. role in the malignant transformation of virus-infected cells Most RNa viruses replicate in the cytosol and do not Cancer-Associated Genes Have induce malignant transtormation. The exceptions are retro. Many Functions reverse-transcriptase enzyme and then integrate the tran- Homeostasis in normal tissue is maintained by a highly reg- script into the host's DNA. This process is similar in the cyto- ulated process of cellular proliferation balanced by cell death. pathic retroviruses such as HIV-1 and HIV-2 and in the If there is an imbalance, either at the stage of cellular prolif- transforming retroviruses, which induce changes in the host eration or at the stage of cell death, then a cancerous state will cell that lead to malignant transformation. In some cases, develop Oncogenes and tumor suppressor genes have been retrovirus-induced transformation is related to the presence shown to play an important role in this process, by regulating of oncogenes, or"cancer genes "carried by the retrovirus. either cellular proliferation or cell death. Cancer-associated One of the best-studied transforming retroviruses is the genes can be divided into three categories that reflect these Rous sarcoma virus. This virus carries an oncogene called different activities, summarized in Table 22-1 v-src, which encodes a 60-kDa protein kinase(v-Src)that cat- alyzes the addition of phosphate to tyrosine residues on pro- INDUCTION OF CELLULAR PROLIFERATION teins. The first evidence that oncogenes alone could induce One category of proto-oncogenes and their oncogenic coun- malignant transformation came from studies of the v-src on- terparts encodes proteins that induce cellular proliferation. gene from Rous Sarcoma virus When this oncogene was Some of these proteins function as growth factors or growth cloned and transfected into normal cells in culture, the cells factor receptors. Included among these are sis, which encodes underwent malignant transformation. a form of platelet-derived growth factor, and fms, erbB, and neu,which encode growth-factor receptors. In normal cells, the expression of growth factors and their receptors is care- Oncogenes and Cancer Induction fully regulated. Usually, one population of cells secretes a growth factor that acts on another population of cells that In 1971, Howard Temin suggested that oncogenes might not tion of the second population. Inappropriate expression of rries the receptor for the factor, thus stimulating prolifera- normal cells; indeed, he proposed that a virus might acquire either a growth factor or its receptor can result in uncon- oncogenes from the genome of an infected cell. He called trolled proliferation. these cellular genes proto-oncogenes, or cellular oncogenes Other oncogenes in this category encode products tha (c-onc, to distinguish them from their viral counterparts function in signal-transduction pathways or as transcription (v-onc). In the mid-1970s, I.M. Bishop and H. E Varmus factors. The src and abl oncogenes encode tyrosine kinases, identified a DNA sequence in normal chicken cells that is and the ras oncogene encodes a GTP-binding protein.The homologous to v-src from Rous sarcoma virus. This cellular products of these genes act as signal transducers. The myc, oncogene was designated c-src. Since these early discoveri jun, and fos oncogenes encode transcription factors. Overac numerous cellular oncogenes have been identified. tivity of any of these oncogenes may result in unregulated uence comparisons of viral and cellular oncogenes proliferation. reveal that they are highly conserved in evolution. Although most cellular oncogenes consist of a series of exons and in- INHIBITION OF CELLULAR PROLIFERATION trons, their viral counterparts consist of uninterrupted cod- A second category of cancer-associated genes-called tumor ing sequences, suggesting that the virus might have acquired suppressor genes, or anti-oncogenes-encodes proteins that the oncogene through an intermediate RNA transcript from hich the intron sequences had been removed during RNa sults in unregulated proliferation. The prototype of this cate processing. The actual coding sequences of viral oncogenes gory of oncogenes is Rh, the retinoblastoma gene Hereditary and the corresponding proto-oncogenes exhibit a high de- retinoblastoma is a rare childhood cancer, in which tumors gree of homology; in some cases, a single point mutation is develop from neural precursor cells in the immature retina. all that distinguishes a viral oncogene from the correspond- The affected child has inherited a mutated Rb allele; somatic ing proto-oncogene. It has now become apparent that most, inactivation of the remaining Rballele leads to tumor growth. if not all, oncogenes(both viral and cellular)are derived from Probably the single most frequent genetic abnormality in cellular genes that encode various growth-controlling pro- human cancer is mutation in p53, which encodes a nuclear teins. In addition, the proteins encoded by a particular onco- phosphoprotein. Over 90% of small-cell lung cancers and
which integrate randomly into the host chromosomal DNA, include several genes that are expressed early in the course of viral replication. SV40 encodes two early proteins called large T and little T, and polyoma encodes three early proteins called large T, middle T, and little T. Each of these proteins plays a role in the malignant transformation of virus-infected cells. Most RNA viruses replicate in the cytosol and do not induce malignant transformation. The exceptions are retroviruses, which transcribe their RNA into DNA by means of a reverse-transcriptase enzyme and then integrate the transcript into the host’s DNA. This process is similar in the cytopathic retroviruses such as HIV-1 and HIV-2 and in the transforming retroviruses, which induce changes in the host cell that lead to malignant transformation. In some cases, retrovirus-induced transformation is related to the presence of oncogenes, or “cancer genes,” carried by the retrovirus. One of the best-studied transforming retroviruses is the Rous sarcoma virus. This virus carries an oncogene called v-src,which encodes a 60-kDa protein kinase (v-Src) that catalyzes the addition of phosphate to tyrosine residues on proteins. The first evidence that oncogenes alone could induce malignant transformation came from studies of the v-src oncogene from Rous sarcoma virus. When this oncogene was cloned and transfected into normal cells in culture, the cells underwent malignant transformation. Oncogenes and Cancer Induction In 1971, Howard Temin suggested that oncogenes might not be unique to transforming viruses but might also be found in normal cells; indeed, he proposed that a virus might acquire oncogenes from the genome of an infected cell. He called these cellular genes proto-oncogenes, or cellular oncogenes (c-onc), to distinguish them from their viral counterparts (v-onc). In the mid-1970s, J. M. Bishop and H. E. Varmus identified a DNA sequence in normal chicken cells that is homologous to v-src from Rous sarcoma virus. This cellular oncogene was designated c-src. Since these early discoveries, numerous cellular oncogenes have been identified. Sequence comparisons of viral and cellular oncogenes reveal that they are highly conserved in evolution. Although most cellular oncogenes consist of a series of exons and introns, their viral counterparts consist of uninterrupted coding sequences, suggesting that the virus might have acquired the oncogene through an intermediate RNA transcript from which the intron sequences had been removed during RNA processing. The actual coding sequences of viral oncogenes and the corresponding proto-oncogenes exhibit a high degree of homology; in some cases, a single point mutation is all that distinguishes a viral oncogene from the corresponding proto-oncogene. It has now become apparent that most, if not all, oncogenes (both viral and cellular) are derived from cellular genes that encode various growth-controlling proteins. In addition, the proteins encoded by a particular oncogene and its corresponding proto-oncogene appear to have very similar functions. As described below, the conversion of a proto-oncogene into an oncogene appears in many cases to accompany a change in the level of expression of a normal growth-controlling protein. Cancer-Associated Genes Have Many Functions Homeostasis in normal tissue is maintained by a highly regulated process of cellular proliferation balanced by cell death. If there is an imbalance, either at the stage of cellular proliferation or at the stage of cell death, then a cancerous state will develop. Oncogenes and tumor suppressor genes have been shown to play an important role in this process, by regulating either cellular proliferation or cell death. Cancer-associated genes can be divided into three categories that reflect these different activities, summarized in Table 22-1. INDUCTION OF CELLULAR PROLIFERATION One category of proto-oncogenes and their oncogenic counterparts encodes proteins that induce cellular proliferation. Some of these proteins function as growth factors or growthfactor receptors. Included among these are sis, which encodes a form of platelet-derived growth factor, and fms, erbB, and neu, which encode growth-factor receptors. In normal cells, the expression of growth factors and their receptors is carefully regulated. Usually, one population of cells secretes a growth factor that acts on another population of cells that carries the receptor for the factor, thus stimulating proliferation of the second population. Inappropriate expression of either a growth factor or its receptor can result in uncontrolled proliferation. Other oncogenes in this category encode products that function in signal-transduction pathways or as transcription factors. The src and abl oncogenes encode tyrosine kinases, and the ras oncogene encodes a GTP-binding protein. The products of these genes act as signal transducers. The myc, jun, and fos oncogenes encode transcription factors. Overactivity of any of these oncogenes may result in unregulated proliferation. INHIBITION OF CELLULAR PROLIFERATION A second category of cancer-associated genes—called tumorsuppressor genes, or anti-oncogenes—encodes proteins that inhibit excessive cell proliferation. Inactivation of these results in unregulated proliferation. The prototype of this category of oncogenes is Rb, the retinoblastoma gene. Hereditary retinoblastoma is a rare childhood cancer, in which tumors develop from neural precursor cells in the immature retina. The affected child has inherited a mutated Rb allele; somatic inactivation of the remaining Rb allele leads to tumor growth. Probably the single most frequent genetic abnormality in human cancer is mutation in p53, which encodes a nuclear phosphoprotein. Over 90% of small-cell lung cancers and Cancer and the Immune System CHAPTER 22 503
504 art Iv The Immune System in Health and disease TABLE 22-1 Functional classification of cancer-associated genes lype/name Nature af gene product ATEGORY L: GENES THAT INDUCE CELLULAR PROLIFERATION Growth factors A form of platelet-derived growth factor(PDGF) Growth-factor receptors Receptor for colony-stimulating factor 1(CSF-1) Receptor for epidermal growth factor(EGF) Protein(HER2)related to EGF receptor Receptor for thyroid hormone lyrosine kinase Ha-ras GTP-binding protein with GTPase activity N-ras GTP-binding protein with GTPase activity K-ras GTP-binding protein with GTPase activity Transcription factors Component of transcription factor AP fos Component of transcription factor AP ayc DNA-binding protein CATEGORY II: TUMOR SUPRESSOR GENES. INHIBITORS OF CELLULAR PROLIFERATION Rb Suppressor of retinoblastoma Nuclear phosphoprotein that inhibits formation of small-cell lung cander and colon cancers DCC pressor of colon carcinoma pressor of adenomatous polyposis NFl Suppressor of neurofibromatosis WIT Suppressor of Wilms tumor CATEGORY III: GENES THAT REGULATE PROGRAMMED CELL DEATH The activity of the normal products of the category ll genes inhibits progression of the cell cycle. Loss of a gene or its inactivation by mutation in an indicated tumor-suppressor gene is associated with development of the indicated cancers. 50% of breast and colon cancers have been shown to be Proto-Oncogenes Can Be Converted ed with mutations in p5. to Oncogenes REGULATION OF PROGRAMMED CELL DEATH In 1972, R J. Huebner and G I Todaro suggested that muta A third category of cancer-associated genes regulates pro- tions or genetic rearrangements of proto-oncogenes by car- grammed cell death. These genes encode proteins that either cinogens or viruses might alter the normally regulated function block or induce apoptosis. Included in this category of onco- of these genes, converting them into potent cancer-causing genes is bcl-2, an anti-apoptosis gene. This oncogene was oncogenes( Figure 22-2). Considerable evidence supporting originally discovered because of its association with B-cell fol- this hypothesis accumulated in subsequent years. For example licular lymphoma. Since its discovery, bd-2 has been shown to some malignantly transformed cells contain multiple copies of lay an important role in regulating cell survival cellular oncogenes, resulting in increased production of onco hematopoiesis and in the survival of selected B cells and gene products. Such amplification of cellular oncogenes has T cells during maturation. Interestingly, the Epstein-Barr been observed in cells from various types of human cancers. virus contains a gene that has sequence homology to bd-2 Several groups have identified c-myc oncogenes in homo- and may act in a similar manner to suppress apoptosis. geneously staining regions(HSRs)of chromosomes from can
over 50% of breast and colon cancers have been shown to be associated with mutations in p53. REGULATION OF PROGRAMMED CELL DEATH A third category of cancer-associated genes regulates programmed cell death. These genes encode proteins that either block or induce apoptosis. Included in this category of oncogenes is bcl-2, an anti-apoptosis gene. This oncogene was originally discovered because of its association with B-cell follicular lymphoma. Since its discovery, bcl-2 has been shown to play an important role in regulating cell survival during hematopoiesis and in the survival of selected B cells and T cells during maturation. Interestingly, the Epstein-Barr virus contains a gene that has sequence homology to bcl-2 and may act in a similar manner to suppress apoptosis. Proto-Oncogenes Can Be Converted to Oncogenes In 1972, R. J. Huebner and G. J. Todaro suggested that mutations or genetic rearrangements of proto-oncogenes by carcinogens or viruses might alter the normally regulated function of these genes, converting them into potent cancer-causing oncogenes (Figure 22-2). Considerable evidence supporting this hypothesis accumulated in subsequent years. For example, some malignantly transformed cells contain multiple copies of cellular oncogenes, resulting in increased production of oncogene products. Such amplification of cellular oncogenes has been observed in cells from various types of human cancers. Several groups have identified c-myc oncogenes in homogeneously staining regions (HSRs) of chromosomes from can- 504 PART IV The Immune System in Health and Disease TABLE 22-1 Functional classification of cancer-associated genes Type/name Nature of gene product CATEGORY I: GENES THAT INDUCE CELLULAR PROLIFERATION Growth factors sis A form of platelet-derived growth factor (PDGF) Growth-factor receptors fms Receptor for colony-stimulating factor 1 (CSF-1) erbB Receptor for epidermal growth factor (EGF) neu Protein (HER2) related to EGF receptor erbA Receptor for thyroid hormone Signal transducers src Tyrosine kinase abl Tyrosine kinase Ha-ras GTP-binding protein with GTPase activity N-ras GTP-binding protein with GTPase activity K-ras GTP-binding protein with GTPase activity Transcription factors jun Component of transcription factor AP1 fos Component of transcription factor AP1 myc DNA-binding protein CATEGORY II: TUMOR-SUPRESSOR GENES, INHIBITORS OF CELLULAR PROLIFERATION* Rb Suppressor of retinoblastoma p53 Nuclear phosphoprotein that inhibits formation of small-cell lung cander and colon cancers DCC Suppressor of colon carcinoma APC Suppressor of adenomatous polyposis NF1 Suppressor of neurofibromatosis WT1 Suppressor of Wilm’s tumor CATEGORY III: GENES THAT REGULATE PROGRAMMED CELL DEATH bcl-2 Suppressor of apoptosis * The activity of the normal products of the category II genes inhibits progression of the cell cycle. Loss of a gene or its inactivation by mutation in an indicated tumor-suppressor gene is associated with development of the indicated cancers
Cancer and the Immune System CHAPTER 22 505 Normal cells Transformed cells gene. For example, avian leukosis virus(ALv) is a retrovirus that does not carry any viral oncogenes and yet is able to trans form B cells into lymphomas. This particular retrovirus has Retroviral been shown to integrate within the c-myc proto-oncogene, transduction which contains three exons. Exon 1 of c-myc has an unknown function; exons 2 and 3 encode the Myc protein Insertion of avl between exon i and exon 2 has been shown in some cases allow the provirus promoter to increase transcription of Mutagens, viruses. exons 2 and 3, resulting in increased synthesis of c-Myc. Expression radiation, and genetic A variety of tumors have been shown to express signifi- cantly increased levels of growth factors or growth-factor sential growth- Cellular oncogenes Growth-factor Expression (a) Chronic myelogenous leukemia Signal transducers trinuclear factors gelators of programmed ① Qualitatively altered, ell death hyperactive pro chromosome Quantitative alterations (gene amplification or translocation) or decreased levels FIGURE 22-2 Conversion of proto-oncogenes into oncogenes 22 involve mutation, resulting in production of qualitatively different gene products, or DNA amplification or translocation, resulting in increased or decreased expression of gene products. cer cells; these HSRs represent long tandem arrays of amplified 9q+ In addition, some cancer cells exhibit chromosomal trans (b)Burkitt's lymphor locations, usually the movement of a proto-oncogene fror one chromosomal site to another(Figure 22-3). In many cases of Burkitt's lymphoma, for example, c-myc is moved from its normal position on chromosome 8 to a position near the immunoglobulin heavy-chain enhancer on chro mosome 14. As a result of this translocation, synthesis of the c-Myc protein, which functions as a transcription factor Increases Mutation in proto-oncogenes also has been associated ∪cmyr with cellular transformation, and it may be a major mecha- nism by which chemical carcinogens or x-irradiation convert FIGURE 22-3 Chromosomal translocations in(a)chronic myeloge. a proto-oncogene into a cancer-inducing oncogene. For in- nous leukemia(CML) and(b)Burkitts lymphoma. Leukemic cells stance, single-point mutations in c-ras have been detected in from all patients with CML contain the so-called Philadelphia chromo- a significant fraction of several human cancers, including car- some, which results from a translocation between chromosomes 9 cinomas of the bladder, colon, and lung. Some of these muta- and 22. Cancer cells from some patients with Burkitts lymphoma ex- tions appear to reduce the ability of Ras to associate with hibit a translocation that moves part of chromosome 8 to chromo- GTPase-stimulating proteins, thus prolonging the growth- some 14. It is now known that this translocation involves c-myc,a activated state of Ras cellular oncogene. Abnormalities such as these are detected by band. pe Viral integration into the host-cell genome may in itself ing analysis of metaphase chromosomes. Normal chromosomes are rve to convert a proto-oncogene into a transforming onco- shown on the left, and translocated chromosomes on the right
cer cells; these HSRs represent long tandem arrays of amplified genes. In addition, some cancer cells exhibit chromosomal translocations, usually the movement of a proto-oncogene from one chromosomal site to another (Figure 22-3). In many cases of Burkitt’s lymphoma, for example, c-myc is moved from its normal position on chromosome 8 to a position near the immunoglobulin heavy-chain enhancer on chromosome 14. As a result of this translocation, synthesis of the c-Myc protein, which functions as a transcription factor, increases. Mutation in proto-oncogenes also has been associated with cellular transformation, and it may be a major mechanism by which chemical carcinogens or x-irradiation convert a proto-oncogene into a cancer-inducing oncogene. For instance, single-point mutations in c-ras have been detected in a significant fraction of several human cancers, including carcinomas of the bladder, colon, and lung. Some of these mutations appear to reduce the ability of Ras to associate with GTPase-stimulating proteins, thus prolonging the growthactivated state of Ras. Viral integration into the host-cell genome may in itself serve to convert a proto-oncogene into a transforming oncogene. For example, avian leukosis virus (ALV) is a retrovirus that does not carry any viral oncogenes and yet is able to transform B cells into lymphomas. This particular retrovirus has been shown to integrate within the c-myc proto-oncogene, which contains three exons. Exon 1 of c-myc has an unknown function; exons 2 and 3 encode the Myc protein. Insertion of AVL between exon 1 and exon 2 has been shown in some cases to allow the provirus promoter to increase transcription of exons 2 and 3, resulting in increased synthesis of c-Myc. A variety of tumors have been shown to express significantly increased levels of growth factors or growth-factor Cancer and the Immune System CHAPTER 22 505 Normal cells Transformed cells Proto–oncogenes Expression Retroviral transduction Mutagens, viruses, radiation, and genetic predisposition Cellular oncogenes Expression Viral oncogenes Essential growth– controlling proteins Growth factors Growth–factor receptors Signal transducers Intranuclear factors Regulators of programmed cell death 1 Qualitatively altered, hyperactive proteins 2 Quantitative alterations (gene amplification or translocation) resulting in increased or decreased levels of products FIGURE 22-2 Conversion of proto-oncogenes into oncogenes can involve mutation, resulting in production of qualitatively different gene products, or DNA amplification or translocation, resulting in increased or decreased expression of gene products. (a) Chronic myelogenous leukemia 9 22 Philadelphia chromosome (b) Burkitt's lymphoma 8 14 9 q+ 22 q– CH VH CH c–myc c–myc VH 8 q– 14 q+ FIGURE 22-3 Chromosomal translocations in (a) chronic myelogenous leukemia (CML) and (b) Burkitt’s lymphoma. Leukemic cells from all patients with CML contain the so-called Philadelphia chromosome, which results from a translocation between chromosomes 9 and 22. Cancer cells from some patients with Burkitt’s lymphoma exhibit a translocation that moves part of chromosome 8 to chromosome 14. It is now known that this translocation involves c-myc, a cellular oncogene. Abnormalities such as these are detected by banding analysis of metaphase chromosomes. Normal chromosomes are shown on the left, and translocated chromosomes on the right