Neoplasia

Benign Tumors

In general, benign tumors are designated by attaching the suffix - oma to the cell type from which the tumor arises. For example, a benign tumor of fibroblasts is a fibroma ; a benign cartilaginous tumor is a chondroma. More complex nomenclature is used for benign epithelial tumors.

• Adenoma is applied to most benign epithelial neoplasms, including those that produce glandlike structures and those that do not.

• Papilloma refers to a benign epithelial neoplasm that produces microscopic or macroscopic fingerlike fronds ( eFig. 6.1 ).

• Polyp refers to a mass that projects above a mucosal surface to form a macroscopically visible structure ( Fig. 6.1 ). Although this term is commonly used for benign tumors, some malignant tumors may grow as polyps, and other polyps (such as nasal polyps) are not neoplastic but inflammatory in origin.

  

• Cystadenoma refers to hollow cystic mass; these are most common in the ovary ( Chapter 17 ).

Malignant Tumors

The nomenclature of malignant tumors essentially follows that of benign tumors, with certain additions and exceptions. Although the nomenclature of neoplasms is complex (and sometimes inconsistent), students must be familiar with it because it is the means by which a tumor’s nature and significance are conveyed by physicians.

• Malignant neoplasms arising in “solid” mesenchymal tissue or its derivatives are named sarcomas, whereas those arising from the cells of the blood are called leukemias or lymphomas. Sarcomas are designated based on their principal cell type. Thus, a malignant neoplasm comprising fatlike cells is a lipo sarcoma, and a malignant neoplasm composed of chondrocyte-like cells is a chondro sarcoma.

• Although epithelia may be derived from all three germ cell layers, malignant neoplasms of epithelial cells are called carcinomas regardless of the tissue of origin. Thus, malignant neoplasms arising in the renal tubular epithelium (mesoderm), the skin (ectoderm), or lining epithelium of the gut (endoderm) are all considered carcinomas.

• Carcinomas are subdivided further. Carcinomas that grow in a glandular pattern are called adenocarcinomas, and those that produce squamous cells are called squamous cell carcinomas. Sometimes the tissue or organ of origin is specified, as in the designation of renal cell carcinoma. Tumors may show little or no differentiation; these are referred to as poorly differentiated or undifferentiated carcinoma.

The neoplastic cells in a tumor, whether benign or malignant, usually resemble each other, consistent with their origin from a single transformed progenitor cell. In some unusual instances, however, the tumor cells undergo divergent differentiation, creating so-called “mixed tumors.” Mixed tumors are clonal, but the progenitor cell in such tumors has the capacity to differentiate along more than one lineage. One example is mixed tumor of the salivary gland, commonly referred to as pleomorphic adenoma . This benign tumor has epithelial components dispersed throughout a fibromyxoid stroma, sometimes harboring islands of cartilage or bone ( Fig. 6.2 ). 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, and sometimes all three. Teratomas originate from totipotent germ cells, which normally reside in the ovary and testis and may be present in midline embryonic rests. Germ cells have the capacity to differentiate into any of the cell types found in the adult body; therefore, they may give rise to neoplasms that contain elements resembling bone, epithelium, muscle, fat, nerve, and other tissues, mixed together in a helter-skelter fashion ( eFig. 6.2 ).

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 are also other instances of confusing terminology:

• Hamartoma is a mass of disorganized tissue resembling the involved site, such as the lung or the liver. Although historically thought of as developmental malformations, hamartomas have clonal chromosomal aberrations that are acquired through somatic mutations and are best considered unusual benign neoplasms.

• Choristoma is a congenital anomaly consisting of a heterotopic nest of cells. For example, a small nodule of pancreatic tissue may be found in the submucosa of the stomach, duodenum, or small intestine. The designation - oma, connoting a neoplasm, gives these lesions an undeserved gravity, as they are usually trivial.

Differentiation and Anaplasia

Differentiation refers to the extent to which neoplasms resemble their cells of origin; lack of differentiation is called anaplasia . In general, benign neoplasms are composed of well-differentiated cells that closely resemble their normal counterparts. 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 cartilaginous matrix—evidence of morphologic and functional differentiation ( eFig. 6.3 ). In well-differentiated benign tumors, mitoses are usually rare and are of normal configuration.

By contrast, most malignant neoplasms exhibit morphologic alterations that demonstrate their malignant nature. In well-differentiated cancers ( Fig. 6.3 ), these features may be quite subtle. For example, well-differentiated adenocarcinoma of the thyroid gland may contain normal-appearing follicles, its malignant potential being revealed only by invasion into adjacent tissues or metastasis. In addition, cancers may induce stromal responses that are not seen in benign tumors. For example, certain cancers induce a dense, abundant fibrous stroma (desmoplasia), making them hard, “scirrhous” tumors.

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. In some instances, dedifferentiation of apparently mature cells occurs during carcinogenesis. However, other 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. Anaplastic cells often display the following features:

• Cellular and nuclear pleomorphism . Tumor cells and their nuclei show great variation in shape and size ( Fig. 6.4 ). In addition nuclei show hyperchromasia (dark staining), 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 (see Fig. 6.4 ).

• Atypical mitoses, which may be numerous. Multiple spindles may produce tripolar or quadripolar mitotic figures ( Fig. 6.5 ).

  

• Loss of polarity, such that cells grow in sheets, with loss of normal orientation and absence of identifiable growth patterns, 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. For example, benign neoplasms and even well-differentiated cancers of endocrine glands frequently elaborate the hormones characteristic of their cell of origin. Similarly, well-differentiated squamous cell carcinomas produce keratin (see Fig. 6.3 ), just as well-differentiated hepatocellular carcinomas secrete bile. In other instances, unanticipated functions emerge. Some cancers express fetal proteins not produced by comparable cells in the adult. Cancers of nonendocrine origin may also produce so-called “ectopic hormones.” For example, certain lung carcinomas secrete adrenocorticotropic hormone (ACTH), parathyroid hormone–like hormone, insulin, glucagon, and others. More is said about these so-called “paraneoplastic” phenomena later.

Also relevant in the discussion of differentiation and anaplasia is dysplasia, referring to disorderly proliferation. Dysplastic epithelium is recognized by loss of uniformity of individual cells and disturbed architectural orientation. Dysplastic cells exhibit pleomorphism and often possess abnormally large, hyperchromatic nuclei. Mitotic figures are more abundant than usual and frequently appear in the superficial epithelium, an abnormal location. In addition, there is architectural disarray. For example, the usual progressive maturation of tall cells in the basal layer to flattened squames on the surface of squamous epithelium may be lost, such that the epithelium consists of a disordered mixture of dark basal-appearing cells. When dysplastic changes are severe and involve the entire thickness of the epithelium, the lesion is referred to as carcinoma in situ, a preinvasive stage of cancer ( Fig. 6.6 ).

It is important to appreciate that dysplasia is not synonymous with cancer. Mild to moderate dysplasia sometimes regresses completely, particularly if inciting causes are removed. However, dysplasia is often present adjacent to frankly malignant neoplasms (e.g., in lung carcinomas arising in the context of cigarette smoking) and as a general rule marks a tissue as being at increased risk for cancer development.

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. Because benign tumors grow and expand slowly, they usually develop a rim of compressed fibrous tissue, often called the capsule ( Fig. 6.7 ). The capsule consists of extracellular matrix that is deposited by stromal cells such as fibroblasts, which may be activated by the mechanical stress created by compression of normal tissue by the expanding tumor. Encapsulation creates a tissue plane that makes the tumor discrete, moveable (nonfixed), and readily excisable by surgical enucleation. However, not all benign neoplasms are encapsulated. For example, uterine leiomyoma 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 may be difficult to excise. These exceptions are pointed out only to emphasize that, although encapsulation is the rule in benign tumors, the lack of a capsule does not mean a tumor is malignant.

Next to the development of metastases, invasiveness is the feature that most reliably distinguishes cancers from benign tumors ( Fig. 6.8 ). Cancers lack well-defined capsules. There are instances in which a slowly growing malignant tumor, such as follicular carcinoma of thyroid, appears to be encased by a capsule, but careful microscopic examination reveals tiny tongues of tumor 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 complete excision of a malignant tumor is attempted. Pathologists carefully examine the margins of resected tumors to ensure they are devoid of cancer cells (clean surgical margins).

Metastasis

Metastasis is defined by the spread of a tumor to sites that are physically discontinuous with the primary tumor and is one of the hallmarks of malignant tumors. The invasiveness of cancers permits them to penetrate blood vessels, lymphatics, and body cavities, providing opportunities for spread ( Fig. 6.9 ). Overall, approximately 30% of patients with newly diagnosed solid tumors (excluding skin cancers other than melanomas) present with clinically evident metastases, and an additional 20% have occult metastases at the time of diagnosis.

In general, large anaplastic neoplasms are more likely to have metastasized at diagnosis, but there are exceptions. Extremely small cancers may 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 locally invasive but rarely metastasize. It is evident then that the properties of local invasion and metastasis are separable.

A special circumstance involves so-called “blood cancers,” the leukemias and lymphomas. These tumors are derived from blood-forming cells that normally have the capacity to enter the bloodstream and travel to distant sites; as a result, with only rare exceptions, leukemias and lymphomas are assumed to be disseminated at diagnosis and are always considered to be malignant.

Malignant neoplasms disseminate by one of three pathways: (1) seeding within body cavities; (2) lymphatic spread; or (3) hematogenous spread. Spread by seeding occurs when neoplasms invade a body cavity. This mode of dissemination is particularly characteristic of cancers of the ovary, which often cover the peritoneal surfaces widely yet may not invade the underlying tissues. In this instance, the ability to implant and grow at distant sites seems to be separable from the capacity to invade. Neoplasms of the central nervous system, such as a medulloblastoma or ependymoma, may penetrate the cerebral ventricles and be carried by the cerebrospinal fluid until they implant on the meningeal surfaces surrounding the brain or spinal cord.

Lymphatic spread is more typical of carcinomas, whereas hematogenous spread is favored by sarcomas. There are numerous interconnections, however, between the lymphatic and vascular systems, so all forms of cancer may disseminate through either or both systems. The pattern of lymph node involvement depends on the site of the primary neoplasm and the pathways of local lymphatic drainage. Lung carcinomas arising in the respiratory passages metastasize first to the regional bronchial lymph nodes and then to the tracheobronchial and hilar nodes. Carcinoma of the breast usually arises in the upper outer quadrant and spreads first to the axillary nodes; however, medial breast lesions may drain to the nodes along the internal mammary artery. Thereafter, in both instances, the supraclavicular and infraclavicular nodes may be seeded. In some cases, cancer cells travel in lymphatic channels through the immediately proximal nodes only to be trapped in subsequent lymph nodes, producing so-called “skip metastases.” The cells may also traverse all the lymph nodes and reach the vascular compartment by way of the thoracic duct.

A “sentinel lymph node” is the first regional lymph node that receives lymph flow from a primary tumor. It can be identified by injection of dyes or radiolabeled tracers near the primary tumor. Biopsy of sentinel lymph nodes allows determination of the extent of tumor spread and can be used to plan treatment. Of note, although enlargement of nodes near a primary neoplasm should raise concern of metastatic spread, it does not always indicate cancerous involvement. The necrotic cells of the neoplasm and tumor antigens often evoke immunologic responses in draining nodes that lead to reactive hyperplasia (lymphadenitis). Thus, biopsy is necessary to determine if an enlarged lymph node is involved by tumor.

Hematogenous spread of cancers is most likely to occur through the penetration of thin-walled veins instead of thick-walled arteries. With venous invasion, the bloodborne cells often arrest in the first capillary bed they encounter. Since the portal system flows to the liver and caval blood flows to the lungs, the liver and lungs are the most frequent sites of hematogenous dissemination. Cancers arising in organs near the vertebral column such as the thyroid and prostate often embolize through the paravertebral plexus, possibly explaining the proclivity of these cancers to spread to the spine. Other carcinomas, particularly renal cell carcinoma and hepatocellular carcinoma, have a propensity to grow within veins in a snakelike fashion, sometimes extending up the inferior vena cava to the right side of the heart. Remarkably, such intravenous growth may not be accompanied by widespread dissemination.

In addition to the stepwise spread of cancers to the next draining lymph node or capillary bed, other cancers frequently spread to noncontiguous organs. For example, prostatic carcinoma preferentially spreads to bone, bronchogenic carcinoma tends to involve the adrenal glands and the brain, neuroblastoma spreads to the liver and bones, and uveal melanoma spreads to the liver. Conversely, other tissues such as skeletal muscle, although rich in capillaries, are rarely sites of tumor metastases. The molecular basis of such tissue-specific homing of tumor cells is discussed later.

Thus, numerous features of tumors (summarized in Fig. 6.10 ) usually permit the differentiation of benign and malignant neoplasms.

Cancer Incidence

For the year 2018, it is estimated that there were over 17 million cases of cancer and 9.6 million deaths due to cancer worldwide (approximately 26,300 deaths per day). Moreover, due to increasing population size, it is projected that the numbers of cancer cases and deaths worldwide will increase to 24 million and 14.6 million, respectively, by the year 2035. Additional perspective on the prevalence of specific cancers can be gained from national incidence and mortality data. In the United States, it is estimated that the year 2022 will be marked by 1.9 million new cases of cancer and 609,000 cancer deaths. Recent incidence data for the most common forms of cancers in the United States, with the major killers identified, are presented in Fig. 6.11 .

The death rates for certain cancers in the United States have changed over several decades. Since 1995, the cancer death rate has decreased by roughly 20% in men and 10% in women. Among men, 80% of the decrease is attributed to lower death rates for cancers of the lung, prostate, and colon; among women, nearly 60% of the decrease is due to reductions in death rates from breast and colorectal cancers. Decreased use of tobacco products is responsible for the reduction in lung cancer deaths, while improved detection and treatment are responsible for the decrease in death rates for colorectal, female breast, and prostate cancers.

The last half-century has also seen a sharp decline in death rates from cervical cancer and gastric cancer in the United States. The decrease in cervical cancer is directly attributable to widespread use of the Papanicolaou (Pap) test for early detection of this tumor and its precursor lesions. The widespread deployment of the human papillomavirus (HPV) vaccine may nearly eliminate this cancer in coming years. The cause of the decline in death rates for cancer of the stomach is obscure; it may be related to decreasing exposure to unknown dietary carcinogens.

Environmental Factors

Environmental exposures are dominant risk factors for many common cancers, suggesting that many cancers are preventable. This notion is supported by the geographic variation in death rates from specific cancers, 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 gastric carcinoma in men and women is about seven times higher in Japan than in the United States. Hepatocellular carcinoma is the most lethal cancer in many parts of Africa. Most evidence suggests that these geographic differences have environmental origins. For example, Nisei (second-generation 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.

There is no paucity of environmental factors that contribute to cancer. They are present in the ambient environment, in the workplace, in food, and in personal practices. Some are universal (e.g., sunlight) whereas others are largely restricted to urban settings (e.g., asbestos) or particular occupations ( Table 6.2 ). The most important environmental exposures linked to cancer include the following:

• Diet. Certain features of diet have been implicated as predisposing influences. More broadly, obesity, currently epidemic in the United States and other parts of the world, is associated with a modestly increased risk for developing many cancers.

• Smoking, particularly of cigarettes, is linked to 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. Excess alcohol intake is an independent risk factor for cancers of the oropharynx, larynx, esophagus, breast, and (due to alcoholic cirrhosis) liver. Moreover, alcohol and tobacco smoking act synergistically to 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 are estimated to cause approximately 15% of cancers worldwide (discussed later).

Age and Cancer

In general, the frequency of cancer increases with age. Most cancer deaths occur between 55 and 75 years of age; the rate declines, along with the population base, after 75 years of age. The rising incidence with age is explained by the accumulation of somatic mutations in cells that drive the emergence of malignant neoplasms (discussed later), and by the decline in immune surveillance that accompanies aging.

Although cancer preferentially affects older adults, it is also responsible for slightly more than 10% of all deaths among children younger than 15 years of age ( Chapter 5 ). The major lethal cancers in children are tumors of the central nervous system, leukemias, lymphomas, and soft tissue and bone sarcomas. As discussed later, study of childhood tumors such as retinoblastoma has provided fundamental insights into the pathogenesis of malignant transformation.

Acquired Predisposing Conditions

Acquired conditions that predispose to cancer include chronic inflammatory disorders, 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 characterized by disturbances of epithelial differentiation that are associated with an elevated risk of carcinoma. They may arise secondary to chronic inflammation or hormonal imbalances (in endocrine-sensitive tissues) or occur spontaneously. Molecular analyses have shown that precursor lesions often possess some of the same genetic lesions that are 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.

Many different precursor lesions have been described; among the most common are the following:

• Squamous metaplasia and dysplasia of bronchial mucosa, seen in habitual smokers—a risk factor for lung carcinoma ( Chapter 11 )

• Endometrial hyperplasia and dysplasia, seen in women with unopposed estrogenic stimulation, is a risk factor for endometrial carcinoma ( Chapter 17 )

• Leukoplakia of the oral cavity, vulva, and penis, which may progress to squamous cell carcinoma ( Chapters 13 , 16 , and 17 )

• Villous adenoma of the colon is associated with a high risk for progression to colorectal carcinoma ( Chapter 13 )

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; it may be better to say that each type of benign tumor is associated with a particular level of risk, ranging from high to virtually nonexistent. For example, adenomas of the colon undergo malignant transformation in up to 50% of cases, whereas malignant change is extremely rare in uterine leiomyomas.

Interactions Between Environmental and Genetic Factors

Certain cancers are hereditary, usually due to germline mutations that affect the function of a gene that suppresses cancer (a so-called “tumor suppressor gene,” discussed later). What then can be said about the influence of heredity on “sporadic” malignant neoplasms, which constitute roughly 95% of the cancers in the United States? While the evidence suggests that sporadic cancers are largely attributable to environmental factors or acquired predisposing conditions, it may be difficult to tease out hereditary and genetic contributions because environmental and genetic factors often interact. Such interactions may be particularly complex when tumor development is affected by small contributions from multiple genes. 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.”

Driver and Passenger Mutations

Driver mutations are mutations that alter the function of cancer genes and thereby directly contribute to the development or progression of cancer. They are usually acquired, but as mentioned earlier, occasionally inherited. By contrast, passenger mutations are acquired mutations that are neutral in terms of fitness and do not affect cellular behavior. Because they occur at random, passenger mutations are sprinkled throughout the genome, whereas driver mutations tend to be tightly clustered within cancer genes. It is now appreciated that passenger mutations may greatly outnumber driver mutations, particularly in cancers caused by carcinogen exposure, such as melanoma and smoking-related lung cancer.

Although apparently innocuous in nature, passenger mutations are important in several ways:

• In carcinogen-associated cancers, analysis of passenger mutations has provided definitive evidence that most genomic damage is directly caused by the carcinogen in question. For example, before sequencing of melanoma genomes, the causative role of sun exposure in this cancer was debated. This is no longer so, as most melanomas have thousands of passenger mutations of a type that is specifically linked to damage caused by ultraviolet light.

• One effect of passenger mutations is that they create genetic variants that, while initially neutral, may provide tumor cells with a selective advantage in the setting of therapy. The evidence for this comes from DNA sequence analyses of tumors at the time of recurrence after drug therapy. In many instances, mutations that lead directly to drug resistance are found in most tumor cells, generally in the target of the drug (e.g., a tyrosine kinase like BCR-ABL, described later). Generally, the same resistance mutations can also be found before therapy, but only in a very small fraction of cells. In such instances, it appears that the selective pressure of therapy “converts” a neutral passenger mutation into a driver mutation, contributing to tumor progression.

• Passenger mutations produce altered proteins that elicit host immune responses. The significance of this will become apparent when we discuss cancer immunity and immunotherapy.

Gene Amplifications

Proto-oncogenes may be converted to oncogenes by gene amplification, with consequent overexpression and hyperactivity of otherwise normal proteins. Such amplification may produce up to several hundred copies of a gene, a change in copy number that is readily detected by molecular hybridization with appropriate DNA probes. In some cases, the amplified genes produce chromosomal changes that can be identified microscopically. Two patterns are seen: (1) multiple small, extrachromosomal structures called double minutes and (2) homogeneously staining regions . The latter derive from the insertion of the amplified genes into new chromosomal locations, which may be distant from the normal location of the involved genes. Because regions containing amplified genes lack normal banding, they have a homogeneous staining pattern in a G-banded karyotype. Two clinically important examples of amplification involve the MYCN gene in neuroblastoma and the HER2 gene in breast cancers. In 25% to 30% of neuroblastomas, MYCN is amplified, a feature that is associated with poor prognosis ( Fig. 6.13 ). HER2 (also known as ERBB2 ) amplification occurs in about 20% of breast cancers, and therapy directed against the receptor encoded by the HER2 gene is highly effective in this subset of tumors.

Epigenetic Modifications and Cancer

You will recall from Chapter 4 that epigenetics refers to reversible, heritable changes in gene expression that occur without mutation. Such changes involve posttranslational modifications of histones and DNA methylation, both of which affect gene expression. In normal, differentiated cells, a large portion of the genome is not expressed. These regions of the genome are silenced by DNA methylation and histone modifications. On the other hand, cancer cells are characterized by global DNA hypomethylation and selective promoter-localized hypermethylation. Indeed, it has become evident that tumor suppressor genes are sometimes silenced by hypermethylation of promoter sequences, rather than by mutation. In addition, genome-wide hypomethylation has been shown to cause chromosomal instability and to induce tumors in mice. Thus, epigenetic changes may influence carcinogenesis in many ways. As an added wrinkle, deep sequencing of cancer genomes has identified mutations in genes that regulate epigenetic modifications in many cancers. Thus, certain genetic changes in cancers may be selected because they lead to epigenetic alterations (e.g., DNA methylation and histone modifications) that favor cancer growth and survival.

Self-Sufficiency in Growth Signals

The self-sufficiency in growth that characterizes cancer cells generally stems from gain-of-function mutations that convert proto-oncogenes to oncogenes. Oncogenes encode proteins called oncoproteins that promote cell growth even in the absence of normal growth-promoting signals. To appreciate how oncogenes drive inappropriate cell growth, it is helpful to review the sequence of events that characterize normal cell proliferation. Under physiologic conditions, signals that drive cell proliferation can be resolved into the following steps:

• 1.

  Binding of a growth factor to its specific receptor on the cell membrane

• 2.

  Transient and limited activation of the growth factor receptor, which in turn activates several signal-transducing proteins on the inner leaflet of the plasma membrane

• 3.

  Transmission of the transduced signal across the cytosol to the nucleus by second messengers or a cascade of signal transduction molecules

• 4.

  Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription and thus the biosynthesis of other cellular components that are needed for cell division, such as organelles, membrane components, and ribosomes

• 5.

  Entry and progression of the cell into the cell cycle, resulting ultimately in cell division

The mechanisms that endow cancer cells with the ability to proliferate can be grouped according to their role in the growth factor–induced signal transduction cascade and cell cycle regulation. Indeed, each one of the steps listed above is susceptible to perturbation in cancer cells.