Empfohlen
Weitere ähnliche Inhalte
Was ist angesagt?
Was ist angesagt? (20)
Ähnlich wie 8. neoplasia
Ähnlich wie 8. neoplasia (20)
Mehr von NkosinathiManana2
Mehr von NkosinathiManana2 (20)
Kürzlich hochgeladen
Kürzlich hochgeladen (20)
8. neoplasia
- 1. Neoplasia 1 Themba Hospital FCOG(SA) Part 1 Tutorials By Dr N.E Manana
- 2. Intro • Cancer is the second leading cause of death in the United States; only cardiovascular diseases exact a higher toll. • Even more agonizing than the associated mortality is the emotional and physical suffering inflicted by neoplasms • Cancer is not one disease but rather many disorders that share a profound growth dysregulation • Cancer is a genetic disorder caused by DNA mutations
- 3. Intro • Genetic alterations in cancer cells are heritable, being passed to daughter cells upon cell division • Mutations and epigenetic alterations impart to cancer cells a set of properties that are referred to collectively as cancer hallmarks • These properties produce the cellular phenotypes that dictate the natural history of cancers as well as their response to various therapies
- 4. NOMENCLATURE • Neoplasia literally means “new growth.” • Neoplastic cells are said to be transformed because they continue to replicate, apparently oblivious to the regulatory influences that control normal cells • A tumor is said to be benign when its microscopic and gross characteristics are considered to be relatively innocent • Malignant, as applied to a neoplasm, implies that the lesion can invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death.
- 5. Benign Tumors • Benign tumors are designated by attaching the suffix -oma to the cell type from which the tumor arises • For example, a benign tumor arising in fibrous tissue is a fibroma; a benign cartilaginous tumor is a chondroma • More varied and complex nomenclature is applied to benign epithelial tumors
- 6. Malignant Tumors • The nomenclature of malignant tumors essentially follows that of benign tumors, with certain additions and exceptions • Malignant neoplasms arising in “solid” mesenchymal tissues or its derivatives are called sarcomas • Whereas those arising from the mesenchymal cells of the blood are called leukemias or lymphomas • Epithelial cells are called carcinomas regardless of the tissue of origin and are subdivided further.
- 7. • Figure 6.1
- 8. Malignant Tumors • The transformed cells in a neoplasm, whether benign or malignant, usually resemble each other, consistent with their origin from a single transformed progenitor cell • However, the tumor cells undergo divergent differentiation, creating so-called “mixed tumors”. • Mixed tumors are still of monoclonal origin, but the progenitor cell in such tumors has the capacity to differentiate down more than one lineage • Teratoma is a special type of mixed tumor that contains recognizable mature or immature cells or tissues derived from more than one germ cell layer
- 9. • Table 6.1
- 10. CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS • There are three fundamental features by which most benign and malignant tumors can be distinguished: Differentiation (anaplasia) Local invasion and metastasis Rapid growth also signifies malignancy, but many malignant tumors grow slowly and as a result growth rate is not a reliable discriminator
- 11. Differentiation and Anaplasia • Differentiation refers to the extent to which neoplasms resemble their parenchymal cells of origin, both morphologically and functionally; lack of differentiation is called anaplasia • Benign neoplasms are composed of well-differentiated cells that closely resemble their normal counterparts • By contrast, while malignant neoplasms exhibit a wide range of parenchymal cell differentiation, most exhibit morphologic alterations that betray their malignant nature • In well-differentiated cancers, these features may be quite subtle
- 12. • Figure 6.3 and Figure 6.4
- 13. Differentiation and Anaplasia • Tumors composed of undifferentiated cells are said to be anaplastic, a feature that is a reliable indicator of malignancy. • The term anaplasia literally means “backward formation” —implying dedifferentiation, or loss of the structural and functional differentiation of normal cells • Anaplastic cells often display the following morphologic features: Pleomorphism Nuclear abnormalities Tumor giant cells Atypical mitoses Loss of polarity
- 14. Local Invasion • The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of surrounding tissues • Whereas most benign tumors grow as cohesive expansile masses that remain localized to their sites of origin • Because benign tumors grow and expand slowly, they usually develop a rim of compressed fibrous tissue • Development of metastases, invasiveness is the feature that most reliably distinguishes cancers from benign tumors
- 15. Metastasis • Metastasis is defined by the spread of a tumor to sites that are physically discontinuous with the primary tumor • And unequivocally marks a tumor as malignant, as by definition benign neoplasms do not metastasize • The invasiveness of cancers permits them to penetrate into blood vessels, lymphatics, and body cavities, providing opportunities for spread • In general, the more anaplastic and the larger the primary neoplasm, the more likely is metastatic spread
- 16. • Figure 6.12
- 17. Environmental Factors • Environmental exposures appear to be the dominant risk factors for many common cancers, suggesting that a high fraction of cancers are potentially preventable • The most important environmental exposures linked to cancer include the following: Diet Smoking Alcohol consumption Reproductive history Infectious agents.
- 18. • Figure 6.13
- 19. • Table 6.2
- 20. Age and Cancer • In general, the frequency of cancer increases with age. • Most cancer deaths occur between 55 and 75 years of age • The rising incidence with age may be explained by the accumulation of somatic mutations that drive the emergence of malignant neoplasms • The decline in immune competence that accompanies aging also may be a factor.
- 21. Acquired Predisposing Conditions • Table 6.3
- 22. Precursor lesions Most common are the following: • Squamous metaplasia and dysplasia of bronchial mucosa, seen in in habitual smokers—a risk factor for lung carcinoma • Endometrial hyperplasia and dysplasia, seen in women with unopposed estrogenic stimulation—a risk factor for endometrial carcinoma • Leukoplakia of the oral cavity, vulva, and penis, which may progress to squamous cell carcinoma • Villous adenoma of the colon, associated with a high risk for progression to colorectal carcinoma
- 23. Environmental and Genetic Factors • Cancer behaves like an inherited trait in some families, usually due to germ line mutations that affect the function of a gene that suppresses cancer • Sporadic cancers can largely be attributed to environmental factors or acquired predisposing conditions, • Lack of family history does not preclude an inherited component
- 24. CANCER GENES • Cancer genes can be defined as genes that are recurrently affected by genetic aberrations in cancers, presumably because they contribute directly to the malignant behavior of cancer cells. • Causative mutations that give rise to cancer genes may be acquired by the action of environmental agents, such as chemicals, radiation, or viruses, may occur spontaneously, or may be inherited in the germ line • Cancer genes fall into one of four major functional classes: Oncogenes, Tumor suppressor genes, Genes that regulate apoptosis AND genes that regulate interactions between tumor cells and host cells
- 25. • Table 6.4
- 26. • Figure 6.14
- 27. CARCINOGENESIS • Fortunately, in most if not all instances, no single mutation is sufficient to transform a normal cell into a cancer cell. • Carcinogenesis is thus a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype and all of its associated hallmarks
- 28. • Figure 6.16
- 29. HALLMARKS OF CANCER • Figure 6.17
- 30. Cyclins and Cyclin-Dependent Kinases • Growth factors transduce signals that stimulate the orderly progression of cells through the various phases of the cell cycle • Progression of cells through the cell cycle is orchestrated by cyclin- dependent kinases (CDKs), which are activated by binding to cyclins, • The CDK-cyclin complexes phosphorylate crucial target proteins that drive cells forward through the cell cycle. • While cyclins arouse the CDKs, CDK inhibitors (CDKIs), of which there are many, silence the CDKs and exert negative control over the cell cycle.
- 31. Insensitivity to Growth Inhibitory Signals • Disruption of such genes renders cells refractory to growth inhibition and mimics the growth-promoting effects of oncogenes • In principle, anti-growth signals can prevent cell proliferation by several complementary mechanisms. • The signal may cause dividing cells to enter G0 (quiescence), where they remain until external cues prod their re-entry into the proliferative pool • RB, a key negative regulator of the cell cycle, is directly or indirectly inactivated in most human cancers
- 32. • Figure 6.20
- 33. TP53: Guardian of the Genome • The p53-encoding tumor suppressor gene, TP53, is the most commonly mutated gene in human cancer. • The p53 protein is a transcription factor that thwarts neoplastic transformation by three interlocking mechanisms: activation of temporary cell cycle arrest (termed quiescence), induction of permanent cell cycle arrest (termed senescence), or triggering of programmed cell death (termed apoptosis) • If RB is a “sensor” of external signals, p53 can be viewed as a central monitor of internal stress, directing the stressed cells toward one of these pathways
- 34. • Figure 6.21
- 35. Thank you
Hinweis der Redaktion
- Some cancers, such as Hodgkin lymphoma, are highly curable, whereas others, such as cancer of the pancreas, are virtually always fatal. The only hope for controlling cancer lies in learning more about its pathogenesis, and great strides have been made in understanding the molecular basis of cancer Most pathogenic mutations are either induced by exposure to mutagens or occur spontaneously as part of aging. In addition, cancers frequently show epigenetic changes, such as focal increases in DNA methylation and alterations in histone modifications, which may themselves stem from acquired mutations in genes that regulate such modifications. These genetic and epigenetic changes alter the expression or function of key genes that regulate fundamental cellular processes, such as growth, survival, and senescence
- Neoplasms therefore enjoy a degree of autonomy and tend to increase in size regardless of their local environment. Their autonomy is by no means complete, however. All neoplasms depend on the host for their nutrition and blood supply. Neoplasms derived from hormone responsive tissues often also require endocrine support, and such dependencies sometimes can be exploited therapeutically All tumors, benign and malignant, have two basic components: (1) the parenchyma, made up of transformed or neoplastic cells, and (2) the supporting, host-derived, non-neoplastic stroma, made up of connective tissue, blood vessels, and host-derived inflammatory cells. The parenchyma of the neoplasm largely determines its biologic behavior, and it is this component from which the tumor derives its name. The stroma is crucial to the growth of the neoplasm, since it carries the blood supply and provides support for the growth of parenchymal cells. Although the biologic behavior of tumors largely reflects the behavior of the parenchymal cells, there has been a growing realization that stromal cells and neoplastic cells carry on a two-way conversation that influences the growth of the tumor
- The term adenoma is generally applied not only to benign epithelial neoplasms that produce glandlike structures, but also to benign epithelial neoplasms that are derived from glands but lack a glandular growth pattern. Thus, a benign epithelial neoplasm arising from renal tubule cells and growing in a glandlike pattern is termed an adenoma, as is a mass of benign epithelial cells that produces no glandular patterns but has its origin in the adrenal cortex. Papillomas are benign epithelial neoplasms, growing on any surface, that produce microscopic or macroscopic fingerlike fronds. A polyp is a mass that projects above a mucosal surface, as in the gut, to form a macroscopically visible structure A polyp is a mass that projects above a mucosal surface, as in the gut, to form a macroscopically visible structure (Fig. 6.1). Although this term commonly is used for benign tumors, some malignant tumors also may grow as polyps, whereas other polyps (such as nasal polyps) are not neoplastic but inflammatory in origin. Cystadenomas are hollow cystic masses that typically arise in the ovary
- Sarcomas are designated based on their cell-type composition, which presumably reflects their cell of origin. Thus, a malignant neoplasm comprised of fat-like cells is a liposarcoma, and a malignant neoplasm composed of chondrocyte-like cells is a chondrosarcoma Furthermore, mesoderm may give rise to carcinomas (epithelial), sarcomas (mesenchymal), and hematolymphoid tumors (leukemias and lymphomas) Carcinomas that grow in a glandular pattern are called adenocarcinomas, and those that produce squamous cells are called squamous cell carcinomas
- The best example is mixed tumor of salivary gland. These tumors have obvious epithelial components dispersed throughout a fibromyxoid stroma, sometimes harboring islands of cartilage or bone All of these diverse elements are thought to derive from a single transformed epithelial progenitor cell, and the preferred designation for these neoplasms is pleomorphic adenoma. Fibroadenoma of the female breast is another common mixed tumor. This benign tumor contains a mixture of proliferating ductal elements (adenoma) embedded in loose fibrous tissue (fibroma). Unlike pleomorphic adenoma, only the fibrous component is neoplastic, but the term fibroadenoma remains in common usage
- Teratomas originate from totipotential germ cells such as those that normally reside in the ovary and testis and that are sometimes abnormally present in midline embryonic rests. Germ cells have the capacity to differentiate into any of the cell types found in the adult body; not surprisingly, therefore, they may give rise to neoplasms that contain elements resembling bone, epithelium, muscle, fat, nerve, and other tissues, all thrown together in a helterskelter fashion
- The specific names of the more common neoplasms are presented in Table 6.1. Some glaring inconsistencies may be noted. For example, the terms lymphoma, mesothelioma, melanoma, and seminoma are used for malignant neoplasms. Unfortunately for students, these exceptions are firmly entrenched in medical terminology. There also are other instances of confusing terminology: • Hamartoma is a mass of disorganized tissue indigenous to the particular site, such as the lung or the liver. While traditionally considered developmental malformations, many hamartomas have clonal chromosomal aberrations that are acquired through somatic mutations and on this basis are now considered to be neoplastic. • Choristoma is a congenital anomaly consisting of a heterotopic nest of cells. For example, a small nodule of well-developed and normally organized pancreatic tissue may be found in the submucosa of the stomach, duodenum, or small intestine. The designation -oma, connoting a neoplasm, imparts to these lesions an undeserved gravity, as they are usually of trivial significance.
- A lipoma is made up of mature fat cells laden with cytoplasmic lipid vacuoles, and a chondroma is made up of mature cartilage cells that synthesize their usual cartilaginous matrix—evidence of morphologic and functional differentiation. In well-differentiated benign tumors, mitoses are usually rare and are of normal configuration
- For example, well-differentiated adenocarcinoma of the thyroid gland may contain normal-appearing follicles, its malignant potential being only revealed by invasion into adjacent tissues or metastasis. The stroma carrying the blood supply is crucial to the growth of tumors but does not aid in the separation of benign from malignant ones. The amount of stromal connective tissue does, however, determine the consistency of a neoplasm. Certain cancers induce a dense, abundant fibrous stroma (desmoplasia), making them hard, so-called “scirrhous tumors”
- It is now known, however, that at least some cancers arise from stem cells in tissues; in these tumors, failure of differentiation of transformed stem cells, rather than dedifferentiation of specialized cells, accounts for their anaplastic appearance. Recent studies also indicate that in some cases, dedifferentiation of apparently mature cells occurs during carcinogenesis Pleomorphism (i.e., variation in size and shape) (Fig. 6.4) • Nuclear abnormalities, consisting of extreme hyperchromatism (dark-staining), variation in nuclear size and shape, or unusually prominent single or multiple nucleoli. Enlargement of nuclei may result in an increased nuclear-to-cytoplasmic ratio that approaches 1 :1 instead of the normal 1 : 4 or 1 :6. Nucleoli may attain astounding sizes, sometimes approaching the diameter of normal lymphocytes. • Tumor giant cells may be formed. These are considerably larger than neighboring cells and may possess either one enormous nucleus or several nuclei. • Atypical mitoses, which may be numerous. Anarchic multiple spindles may produce tripolar or quadripolar mitotic figures (Fig. 6.5). • Loss of polarity, such that anaplastic cells lack recognizable patterns of orientation to one another. Such cells may grow in sheets, with total loss of communal structures, such as glands or stratified squamous architecture. Well-differentiated tumor cells are likely to retain the functional capabilities of their normal counterparts, whereas anaplastic tumor cells are much less likely to have specialized functional activities In other instances, unanticipated functions emerge. Some cancers may express fetal proteins not produced by comparable cells in the adult. Cancers of nonendocrine origin may produce so-called “ectopic hormones.” For example, certain lung carcinomas may produce adrenocorticotropic hormone (ACTH), parathyroid hormone– like hormone, insulin, glucagon, and others. More is said about these so-called “paraneoplastic” phenomena later. Also of relevance in the discussion of differentiation and anaplasia is dysplasia, referring to disorderly proliferation.
- This capsule consists largely of extracellular matrix that is deposited by stromal cells such as fibroblasts, which are activated by hypoxic damage to parenchymal cells resulting from compression by the expanding tumor. Encapsulation creates a tissue plane that makes the tumor discrete, moveable (non-fixed), and readily excisable by surgical enucleation. However, it is important to recognize that not all benign neoplasms are encapsulated For example, the leiomyoma of the uterus is discretely demarcated from the surrounding smooth muscle by a zone of compressed and attenuated normal myometrium, but lacks a capsule. A few benign tumors are neither encapsulated nor discretely defined; lack of demarcation is particularly likely in benign vascular neoplasms such as hemangiomas, which understandably may be difficult to excise Cancers lack welldefined capsules. There are instances in which a slowly growing malignant tumor deceptively appears to be encased by the stroma of the surrounding host tissue, but microscopic examination reveals tiny crablike feet penetrating the margin and infiltrating adjacent structures. This infiltrative mode of growth makes it necessary to remove a wide margin of surrounding normal tissue when surgical excision of a malignant tumor is attempted. Surgical pathologists carefully examine the margins of resected tumors to ensure that they are devoid of cancer cells (clean margins)
- Overall, approximately 30% of patients with newly diagnosed solid tumors (excluding skin cancers other than melanomas) present with clinically evident metastases. An additional 20% have occult (hidden) metastases at the time of diagnosis but as with most rules there are exceptions. Extremely small cancers have been known to metastasize; conversely, some large and ominous-looking lesions may not. While all malignant tumors can metastasize, some do so very infrequently. For example, basal cell carcinomas of the skin and most primary tumors of the central nervous system are highly locally invasive but rarely metastasize. It is evident then that the properties of local invasion and metastasis are sometimes separable with only rare exceptions, leukemias and lymphomas are taken to be disseminated diseases at diagnosis and are always considered to be malignant
- This notion is supported by the geographic variation in death rates from specific forms of cancer, which is thought to stem mainly from differences in environmental exposures. For instance, death rates from breast cancer are about four to five times higher in the United States and Europe than in Japan. Conversely, the death rate for stomach carcinoma in men and women is about seven times higher in Japan than in the United States Liver cell carcinoma is relatively infrequent in the United States but is the most lethal cancer among many African populations. Nearly all the evidence indicates that these geographic differences have environmental rather than genetic origins. For example, Nisei (secondgeneration Japanese living in the United States) have mortality rates for certain forms of cancer that are intermediate between those in natives of Japan and in Americans who have lived in the United States for many generations. The two rates come closer with each passing generation
- Diet. Certain features of diet have been implicated as predisposing influences. More broadly, obesity, currently epidemic in the United States, is associated with a modestly increased risk for developing many different cancers. • Smoking. Smoking, particularly of cigarettes, has been implicated in cancer of the mouth, pharynx, larynx, esophagus, pancreas, bladder, and, most significantly, the lung, as 90% of lung cancer deaths are related to smoking. • Alcohol consumption. Alcohol abuse is an independent risk factor for cancers of the oropharynx, larynx, esophagus, and (due to alcoholic cirrhosis) liver. Moreover, alcohol and tobacco smoking synergistically increase the risk for developing cancers of the upper airways and upper digestive tract. • Reproductive history. There is strong evidence that lifelong cumulative exposure to estrogen stimulation, particularly if unopposed by progesterone, increases the risk for developing cancers of the endometrium and breast, both of which are estrogen-responsive tissues. • Infectious agents. It is estimated that infectious agents cause approximately 15% of cancers worldwide.
- Although cancer preferentially affects older adults, it also is responsible for slightly more than 10% of all deaths among children younger than 15 years of age (Chapter 7). The major lethal cancers in children are leukemias, tumors of the central nervous system, lymphomas, and soft-tissue and bone sarcomas. As discussed later, study of several childhood tumors, such as retinoblastoma, has provided fundamental insights into the pathogenesis of malignant transformation.
- Acquired conditions that predispose to cancer include disorders associated with chronic inflammation, immunodeficiency states, and precursor lesions Many chronic inflammatory conditions create a fertile “soil” for the development of malignant tumors (Table 6.3). Tumors arising in the context of chronic inflammation are mostly carcinomas, but also include mesothelioma and several kinds of lymphoma. By contrast, immunodeficiency states mainly predispose to virus-induced cancers, including specific types of lymphoma and carcinoma and some sarcoma-like proliferations Precursor lesions are localized disturbances of epithelial differentiation that are associated with an elevated risk for developing carcinoma. They may arise secondary to chronic inflammation or hormonal disturbances (in endocrine-sensitive tissues), or may occur spontaneously. Molecular analyses have shown that precursor lesions often possess some of the genetic lesions found in their associated cancers (discussed later). However, progression to cancer is not inevitable, and it is important to recognize precursor lesions because their removal or reversal lowers cancer risk
- In this context it also may be asked, “What is the risk for malignant change in a benign neoplasm?”—or, stated differently, “Are benign tumors precancers?” In general the answer is no, but inevitably there are exceptions, and perhaps it is better to say that each type of benign tumor is associated with a particular level of risk, ranging from high to virtually nonexistent. As cited earlier, adenomas of the colon as they enlarge can undergo malignant transformation in up to 50% of cases; by contrast, malignant change is extremely rare in leiomyomas of the uterus
- Furthermore, genetic factors may alter the risk for developing environmentally induced cancers. Instances where this holds true often involve inherited variation in enzymes such as components of the cytochrome P-450 system that metabolize procarcinogens to active carcinogens. Conversely, environmental factors can influence the risk for developing cancer, even in individuals who inherit well-defined “cancer genes.” For instance, breast cancer risk in females who inherit mutated copies of the BRCA1 or BRCA2 tumor suppressor genes (discussed later) is almost three-fold higher for women born after 1940 than for women born before that year, perhaps because of changes in reproductive behavior or increases in obesity in more recent times
- Oncogenes are genes that induce a transformed phenotype when expressed in cells by promoting increased cell growth. A major discovery in cancer was the realization that oncogenes are mutated or overexpressed versions of normal cellular genes, which are called proto-oncogenes. Most oncogenes encode transcription factors, factors that participate in pro-growth signaling pathways, or factors that enhance cell survival. They are considered dominant genes because a mutation involving a single allele is sufficient to produce a pro-oncogenic effect. • Tumor suppressor genes are genes that normally prevent uncontrolled growth and, when mutated or lost from a cell, allow the transformed phenotype to develop. Often both normal alleles of tumor suppressor genes must be damaged for transformation to occur. Tumor suppressor genes can be placed into two general groups, “governors” that act as important brakes on cellular proliferation, and “guardians” that are responsible for sensing genomic damage. Some guardian genes initiate and choreograph a complex “damage control response” that leads to the cessation of proliferation or, if the damage is too great to be repaired, or induce apoptosis. • Genes that regulate apoptosis primarily act by enhancing cell survival, rather than stimulating proliferation per se. Understandably, genes of this class that protect against apoptosis are often overexpressed in cancer cells, whereas those that promote apoptosis tend to be underexpressed or functionally inactivated by mutations. • To this list may now be added genes that regulate interactions between tumor cells and host cells, as these genes are also recurrently mutated or functionally altered in certain cancers. Particularly important are genes that enhance or inhibit recognition of tumors cells by the host immune system
- In most instances, the mutations that give rise to cancer genes are acquired during life and are confined to the cancer cells. However, causative mutations sometimes are inherited in the germ line and are therefore present in every cell in the body, placing the affected individual at high risk for developing cancer. Understandably, in families in which these germ line mutations are passed from generation to generation, cancer behaves like an inherited trait (Table 6.4)
- Other oncogenic gene rearrangements create fusion genes encoding novel chimeric proteins Identification of pathogenic gene rearrangements in carcinomas has lagged because karyotypically evident translocations and inversions (which point to the location of important oncogenes) are rare in carcinomas Deletions are another prevalent abnormality in tumor cells. Deletion of specific regions of chromosomes may result in the loss of particular tumor suppressor genes. Gene Amplifications Proto-oncogenes may be converted to oncogenes by gene amplification, with consequent overexpression and hyperactivity of otherwise normal proteins Aneuploidy is defined as a number of chromosomes that is not a multiple of the haploid state; for humans, that is a chromosome number that is not a multiple of 23
- It is well established that during their course cancers generally become more aggressive and acquire greater malignant potential, a phenomenon referred to as tumor progression. At the molecular level, tumor progression most likely results from mutations that accumulate independently in different cells. Some of these mutations may be lethal, but others may affect the function of cancer genes, thereby making the affected cells more adept at growth, survival, invasion, metastasis, or immune evasion. Due to this selective advantage, subclones that acquire these mutations may come to dominate one area of a tumor, either at the primary site or at sites of metastasis As a result of continuing mutation and Darwinian selection, even though malignant tumors are monoclonal in origin they are typically genetically heterogeneous by the time of their clinical presentation. In advanced tumors exhibiting genetic instability, the extent of genetic heterogeneity may be enormous. Genetic evolution shaped by darwinian selection can explain the two most pernicious properties of cancers: the tendency over time for cancers to become both more aggressive and less responsive to therapy
- It appears that all cancers display eight fundamental changes in cell physiology, which are considered the hallmarks of cancer
- Expression of these inhibitors is downregulated by mitogenic signaling pathways, thus promoting the progression of the cell cycle. There are two main cell cycle checkpoints, one at the G1/S transition and the other at the G2/M transition, each of which is tightly regulated by a balance of growthpromoting and growth-suppressing factors, as well as by sensors of DNA damage If activated, these DNA-damage sensors transmit signals that arrest cell cycle progression and, if cell damage cannot be repaired, initiate apoptosis. Once cells pass through the G1/S checkpoint, they are committed to undergo cell division. Understandably, then, defects in the G1/S checkpoint are particularly important in cancer, since these lead directly to increased cell division. Indeed, all cancers appear to have genetic lesions that disable the G1/S checkpoint, causing cells to continually reenter the S phase. For unclear reasons, particular lesions vary widely in frequency across tumor types, but they fall into two major categories A final consideration of importance in a discussion of growth-promoting signals is that the increased production of oncoproteins does not by itself lead to sustained proliferation of cancer cells. There are two built-in mechanisms, cell senescence and apoptosis, that oppose oncogenemediated cell growth
- Isaac Newton theorized that every action has an equal and opposite reaction. Although Newton was not a cancer biologist, his formulation holds true for cell growth Alternatively, the cells may enter a postmitotic, differentiated pool and lose replicative potential. Nonreplicative senescence, alluded to earlier, is another mechanism of escape from sustained cell growth. And, as a last-ditch effort, the cells may be programmed for death by apoptosis. As we will see, tumor suppressor genes have all these “tricks” in their toolbox designed to halt wayward cells from becoming malignant retinoblastoma gene (RB) was the first tumor suppressor gene to be discovered and is now considered the prototype of this family of cancer genes. As with many advances in medicine, the discovery of tumor suppressor genes was accomplished by the study of a rare disease—in this case, retinoblastoma, an uncommon childhood tumor. Approximately 60% of retinoblastomas are sporadic, while the remaining ones are familial, the predisposition to develop the tumor being transmitted as an autosomal dominant trait
- The initiation of DNA replication (S phase) requires the activity of cyclin E/CDK2 complexes, and expression of cyclin E is dependent on the E2F family of transcription factors. Early in G1, RB is in its hypophosphorylated active form, and it binds to and inhibits the E2F family of transcription factors, preventing transcription of cyclin E. Hypophosphorylated RB blocks E2F-mediated transcription in at least two ways (Fig. 6.20). First, it sequesters E2F, preventing it from interacting with other transcriptional activators. Second, RB recruits chromatin remodeling proteins, such as histone deacetylases and histone methyltransferases, which bind to the promoters of E2F-responsive genes such as cyclin E. These enzymes modify chromatin at the promoters to make DNA insensitive to transcription factors. • This situation is changed on mitogenic signaling. Growth factor signaling leads to cyclin D expression and activation of cyclin D–CDK4/6 complexes. The level of cyclin D-CDK4/6 activity is tempered by antagonists such as p16, which is itself subject to regulation by growth inhibitors such as TGFβ that serve to set a threshold for mitogenic responses. If the stimulus is sufficently strong, cyclin D-CDK4/6 complexes phosphorylate RB, inactivating the protein and releasing E2F to induce target genes such as cyclin E. Cyclin E/CDK complexes then stimulate DNA replication and progression through the cell cycle. When the cells enter S phase, they are committed to divide without additional growth factor stimulation. During the ensuing M phase, the phosphate groups are removed from RB by cellular phosphatases, regenerating the hypophosphorylated form of RB. • E2F is not the sole target of RB. The versatile RB protein binds to a variety of other transcription factors that regulate cell differentiation. For example, RB stimulates myocyte-, adipocyte-, melanocyte-, and macrophagespecific transcription factors. Thus, the RB pathway couples control of cell cycle progression at G1 with differentiation, which may explain how differentiation is associated with exit from the cell cycle. RB phosphorylation can mimic the effect of RB loss and are commonly found in many cancers that have normal RB genes. For example, mutational activation of CDK4 and overexpression of cyclin D favor cell proliferation by facilitating RB phosphorylation and inactivation. Indeed, cyclin D is overexpressed in many tumors because of amplification or translocation of the cyclin D1 gene. Mutational inactivation of genes encoding CDKIs also can drive the cell cycle by removing important brakes on cyclin/ CDK activity. As mentioned earlier, the CDKN2A gene, which encodes the CDK inhibitor p16, is an extremely common target of deletion or mutational inactivation in human tumors. It is now accepted that loss of normal cell cycle control is central to malignant transformation and that at least one of the four key regulators of the cell cycle (p16, cyclin D, CDK4, RB) is mutated in most human cancers Notably, in cancers caused by certain oncogenic viruses (discussed later), this is achieved through direct targeting of RB by viral proteins. For example, the human papillomavirus (HPV) E7 protein binds to the hypophosphorylated form of RB, preventing it from inhibiting the E2F transcription factors. Thus, RB is functionally deleted, leading to uncontrolled growth.
- A variety of stresses trigger the p53 response pathways, including anoxia, inappropriate pro-growth stimuli (e.g., unbridled MYC or RAS activity), and DNA damage. By managing the DNA damage response, p53 plays a central role in maintaining the integrity of the genome, as discussed next. In nonstressed, healthy cells, p53 has a short half-life (20 minutes) because of its association with MDM2, a protein that targets p53 for destruction
- These genes suppress neoplastic transformation by three mechanisms: • p53-mediated cell cycle arrest may be considered the primordial response to DNA damage (Fig. 6.21). It occurs late in the G1 phase and is caused mainly by p53-dependent transcription of the CDKI gene CDKN1A (p21). The p21 protein inhibits cyclin–CDK complexes and prevents phosphorylation of RB, thereby arresting cells in the G1 phase. Such a pause in cell cycling is welcome, because it gives the cells “breathing time” to repair DNA damage. The p53 protein also induces expression of DNA damage repair genes. If DNA damage is repaired successfully, p53 upregulates transcription of MDM2, leading to its own destruction and relief of the cell cycle block. If the damage cannot be repaired, the cell may enter p53- induced senescence or undergo p53-directed apoptosis. • p53-induced senescence is a form of permanent cell cycle arrest characterized by specific changes in morphology and gene expression that differentiate it from quiescence or reversible cell cycle arrest. Senescence requires activation of p53 and/or Rb and expression of their mediators, such as the CDKIs. The mechanisms of senescence are unclear but seem to involve global chromatin changes, which drastically and permanently alter gene expression. • p53-induced apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against neoplastic transformation. It is mediated by upregulation of several proapoptotic genes, including BAX and PUMA (discussed later). To summarize, p53 is activated by stresses such as DNA damage and assists in DNA repair by causing G1 arrest and inducing the expression of DNA repair genes. A cell with damaged DNA that cannot be repaired is directed by p53 to either enter senescence or undergo apoptosis (see Fig. 6.21). In view of these activities, p53 has been rightfully called the “guardian of the genome.” With loss of normal p53 function, DNA damage goes unrepaired, mutations become fixed in dividing cells, and the cell turns onto a one-way street leading to malignant transformation Confirming the importance of TP53 in controlling carcinogenesis, more than 70% of human cancers have a defect in this gene, and the remaining malignant neoplasms often have defects in genes upstream or downstream of TP53