Cancer

group of more than 100 distinct diseases characterized by the uncontrolled growth of abnormal cells in the body. Cancer affects one in every tharee persons born in developed countries and is a major cause of sickness and death throughout the world. Though it has been known since antiquity, significant improvements in cancer treatment have been made since the middle of the 20th century, mainly through a combination of timely and accurate diagnosis, selective surgery, radiation therapy, and chemotherapeutic drugs. Such advances actually have brought about a decrease in cancer deaths (at least in developed countries), and grounds for further optimism are seen in laboratory investigations into elucidating the causes and mechanisms of the disease. Owing to continuing advances in cell biology, genetics, and biotechnology, researchers now have a fundamental understanding of what goes wrong in a cancer cell and in an individual who develops cancer—and these conceptual gains are steadily being converted into further progress in prevention, diagnosis, and treatment of this disease.
This article covers the complex subject of cancer in several sections. The first section, Types of cancer, reviews the major cancer types according to their pattern of growth, site of origin, and other characteristics. Links are provided from diagrams and tables in this section to more detailed entries on specific cancers. Subsequent sections describe the growth and spread of cancerous tumours, their effects on the individual, and methods of diagnosing and treating them. The section Causes of cancer provides a detailed examination of the molecular basis of the disease, the principal cancer-causing agents, and hereditary factors involved in cancer development. Finally, Milestones in cancer science provides a brief overview of cancer science throughout history.
Types of cancer
Malignant tumours and benign tumours
Tumours, or neoplasms (from Greek neo, “new”; plasma, “formation”), are abnormal growths of cells arising from malfunctions in the regulatory mechanisms that oversee the cells' growth and development. The specific factors that cause healthy cells to go awry are explained in Causes of cancer, and the step-by-step growth of these cells into tissue masses is described in The growth and spread of cancer. Here it is sufficient to say that, when normally growing cells are transformed into undisciplined cancer cells, they divide and multiply and form masses of tissue known as tumours. As tumours grow, they invade and destroy nearby healthy tissues. If they gain access to the circulatory or lymphatic systems, tumours can migrate throughout the body, seeding in distant areas (a process known as metastasis). Tumours that grow and spread aggressively in this manner are designated malignant, or cancerous. Left unchecked, they can spread throughout the body and disrupt organs that are necessary to keep an individual healthy and alive.
Some tumours, however, remain localized to the area in which they arise and pose little risk to health. These tumours are called benign. Although benign tumours are indeed abnormal, they are far less dangerous than malignant tumours because they have not entirely escaped the growth controls that keep normal cells in check. They are not aggressive and do not invade surrounding tissues or spread to distant sites. In some cases they even function like the normal cells from which they arise.
Nevertheless, though they are incapable of dissemination, benign tumours do expand and can cause signs or symptoms of disease in an individual by replacing or impinging on an organ. In some cases benign tumours that compress vital structures can kill—for instance, tumours that compress the brainstem, where the centres that control breathing are located. However, it is unusual for a benign tumour to cause the death of an individual.
When the behaviour of a neoplasm is difficult to predict, it is designated as being of “undetermined malignant potential,” or “borderline.”
Tumour nomenclature
“Malignant” and “benign” are two important distinctions, but they are broad categories that comprise many different forms of cancer. A more detailed and useful way to classify and name tumours is by their site of origin (that is, the cell or tissue from which a tumour arises) and by their microscopic appearance. This classification scheme, though not followed with rigid logic or consistency, allows tumours to be categorized by a characteristic prognosis and therapy. Tumour nomenclature thus provides a means of identifying tumours and determining the best course of treatment.
Nomenclature of benign tumours
In the majority of cases, benign tumours are named by attaching the suffix -oma to the name of the tissue or cell from which the cancer arose. For example, a tumour that is composed of cells related to bone cells, and that has the structural and biochemical properties of bone substance (osteoid), is classified as an osteoma. This rule is followed with a few exceptions for tumours that arise from mesenchymal cells (the precursors of bone and muscle).
Benign tumours arising from epithelial cells (cells that form sheets that line the skin and internal organs) are classified in a number of ways and thus have a variety of names. Sometimes classification is based on the cell of origin, whereas in other cases it is based on the tumour's microscopic architectural pattern or gross appearance. The term adenoma, for instance, designates a benign epithelial tumour that either arises in endocrine glands or forms a glandular structure. Tumours of the ovarian epithelium that contain large cysts are called cystadenomas.
When a tumour gives rise to a mass that projects into a lumen (a cavity or channel within a tubular organ), it is called a polyp. Most polyps are epithelial in origin. Strictly speaking, the term polyp should be restricted to designating benign growths; a malignant polyp should be referred to as a polypoid cancer in order to avoid confusion.
Benign tumours built up of fingerlike projections from the skin or mucous membranes are called papillomas.
Nomenclature of malignant tumours
For the naming of malignant tumours, the rules for using prefixes and suffixes are similar to those used to designate benign neoplasms. The suffix -sarcoma indicates neoplasms that arise in mesenchymal tissues—for instance, in supportive or connective tissue such as muscle or bone. The suffix -carcinoma, on the other hand, indicates an epithelial origin. As with benign tumours, a prefix indicates the predominant cell type in the tumour. Thus, a liposarcoma arises from a precursor to a fat cell called a lipoblastic cell; a myosarcoma is derived from precursor muscle cells (myogenic cells); and squamous-cell carcinoma arises from the outer layers of mucous membranes or the skin (composed primarily of squamous, or scalelike, cells).
Just as adenoma designates a benign tumour of epithelial origin that takes on a glandlike structure, so adenocarcinoma designates a malignant epithelial tumour with a similar growth pattern. Usually the term is followed by the organ of origin—e.g., adenocarcinoma of the lung.
Malignant tumours of the blood-forming tissue are designated by the suffix -emia (Greek: “blood”). Thus, leukemia refers to a cancerous proliferation of white blood cells (leukocytes). Cancerous tumours that arise in lymphoid organs, such as the spleen, thymus, or lymph glands, are termed malignant lymphomas. The term lymphoma is often used without the qualifier malignant to denote cancerous lymphoid tumours; however, this usage is confusing, since the suffix -oma, as mentioned above, more properly designates a benign neoplasm.
The suffix -oma is also used to designate other malignancies, such as seminoma, which is a malignant tumour that arises from the germ cells of the testis. In a similar manner, malignant tumours of melanocytes (the skin cells that produce the pigment melanin) should be called melanocarcinomas, but for historical reasons the term melanoma persists.
In some instances neoplasms are named for the physician who first described them. For example, the malignant lymphoma called Hodgkin disease was described in 1832 by the English physician Thomas Hodgkin. Burkitt lymphoma is named after the British surgeon Denis Parsons Burkitt; Ewing sarcoma of bone was described by James Ewing; and nephroblastoma, a malignant tumour of the kidney in children, is commonly called Wilms tumour, for the German surgeon Max Wilms.
Site of origin
The site of origin of a tumour, which is so important in its classification and naming (as explained above), also is an important determinant of the way a tumour will grow, how fast it will give rise to clinical symptoms, and how early it may be diagnosed. For example, a tumour of the skin located on the face is usually detected very early, whereas a sarcoma located in the deep soft tissues of the abdomen can grow to weigh 2 kilograms (5 pounds) before it causes much of a disturbance. The site of origin of a tumour also determines the signs and symptoms of disease that the individual will experience and influences possible therapeutic options.
As is shown in the figure (using estimates from the United States for 2000), the most common tumour sites in females are the breast, lung, and colon. In men the most frequently affected sites are the prostate, lung, and colon. Each tumour site and type presents its own specific set of clinical manifestations. (These manifestations and other details are described in separate entries on each type of cancer, which can be accessed directly from the figure.) However, there are a number of common clinical presentations, or syndromes, caused by many different kinds of tumours (see the section The growth and spread of cancer: Effects of tumours on the individual).
Rates and trends
Statistical records
The risk that an individual faces of developing and dying from cancer is expressed by incidence and mortality rates. (Incidence is the rate of occurrence per year of new cases, and the mortality rate is the number of deaths that occur per year in a particular population divided by the size of the population at that time.) These figures are compiled by tumour registries in many different parts of the world. Statistics kept in developed countries show a decrease in deaths caused by cancer at the end of the 20th century.
One of the most authoritative sources of information on cancer incidence, survival, and mortality is the Surveillance, Epidemiology and End Results (SEER) Program, sponsored by the National Cancer Institute in the United States. Established in 1973, SEER compiles data that cover about 10 percent of the U.S. population. The figures are updated every year and are made available to researchers, public health planners, and legislatures. The data generated by programs like SEER are used to identify geographic and population differences in cancer patterns that point to possible links between cancer incidence and occupation, environment, and lifestyle. For example, throughout the world, cigarette smoking is implicated as a cause of cancer of the lung, mouth, larynx, esophagus, pancreas, and urinary bladder; alcohol is associated with the genesis of cancer of the larynx, pharynx, and esophagus; and obese persons are known to suffer a higher mortality rate from cancer than persons within normal weight limits.
Cancer and age
Cancer is to a great degree a disease of the elderly, and age is thus a very important factor in cancer development. However, individuals of any age, including very young children, can be stricken with the disease. In many developed countries cancer deaths in children are second only to accidental deaths. In the United States, as can be seen in the table, the most striking increase in cancer mortality is seen in persons between the ages of 55 and 75. A decline in cancer mortality in persons older than 75 simply reflects the lower number of persons in that population.
Declining death rates
Age-adjusted death rates (deaths per 100,000 population) for specific types of tumours have changed significantly over the years. In 1996, for the first time since data began being compiled, cancer deaths in the United States decreased (almost 3 percent). Decreases can be attributed to successes of therapy or prevention. For example, a reduction in the number of deaths due to lung cancer is attributed to warnings that have altered cigarette-smoking habits. Therapy has greatly lessened mortality from Hodgkin disease and testicular cancer, and it also has improved the chances of surviving breast cancer. The yearly routine Pap smear, an examination used to screen for carcinoma of the uterine cervix, has resulted in a downward trend in mortality observed for this disease. This reduction in cancer deaths clearly exemplifies the benefits of screening and early detection.
Variation with region and culture
Striking differences in incidence and age-adjusted death rates of specific forms of cancer are seen in various parts of the world. For example, deaths caused by malignant melanoma, a cancer of the pigmented cells in the skin, are six times more frequent in New Zealand than in Iceland, a variation attributed to differences in sun exposure.
Most observed geographic differences probably result from environmental or cultural influences, rather than from differences in the genetic makeup of separate populations. This view is illustrated by examining the differing incidences of stomach cancer that occur in Japanese immigrants to the United States, in Japanese-Americans born to immigrant parents, and in long-term resident populations of both countries. Gastric cancer mortality rates are much higher in Japan than they are in California probably due to dietary and lifestyle differences. Rates for first-generation Japanese immigrants, on the other hand, are intermediate between those of native Japanese and native Californians, and mortality rates among descendants of Japanese immigrants approach those of the general Californian population with each passing generation. Such observable trends clearly suggest that environmental and cultural factors play an important role in the causation of cancer.
Exposure to carcinogens and disease
Exposure to high levels of carcinogens (substances or forms of energy that are known to cause cancer—for instance, asbestos or ionizing radiation) can occur in the workplace. Occupational exposure can result in small epidemics of unusual cancers, such as an increase in angiosarcoma of the liver documented in 1974 among American workers who cleaned vinyl chloride polymerization vessels. (See the table of chemical carcinogens.)
In addition, new or “emerging” diseases can have a drastic influence on cancer rates. Kaposi sarcoma, a rare form of vascular tumour in the Western world, is common among individuals with AIDS (acquired immunodeficiency syndrome), and thus its rate has skyrocketed since 1981, when the AIDS epidemic began.
The growth and spread of cancer
James Ewing, an early 20th-century American pathologist, defined tumours as “semiautonomous growths of tissue.” This definition has stood the test of time because it emphasizes two major features of cancer: abnormal cell growth and the fact that abnormal growth occurs because of a malfunction in the mechanisms that control cell growth and differentiation. The malfunctioning of the cell's control mechanisms is described in detail in another section of this article, Causes of cancer. The current section focuses on stages in the growth of tumours and on the effects of tumours on the individual.
Tumour progression: the clinical view
Presentation
Tumours, both malignant and benign, “present” (that is, first become observable) as lumps or masses caused by the abnormal growth of cells. Many benign tumours are encased in a well-formed capsule. Malignant tumours, on the other hand, lack a true capsule and, even when limited to a specific location, invariably can be seen to have infiltrated surrounding tissues. The ability to invade adjacent tissues is a major characteristic delineating malignant tumours from benign tumours.
A tumour mass is composed not only of abnormal tumour cells but also of normal host cells that have been developed to nourish the tumour as well as immune cells that have been stimulated to react to the tumour. The “healthy” or “normal” component of the tumour is referred to as the tumour stroma.
As stated above, one of the fundamental characteristics of cancer cells is their uncontrolled growth. Through the microscope this behaviour is seen in an increased rate of cell division and in the failure of tumour cells to die. The rate of tumour growth is determined by comparing the excess of cell production with cell loss. For a transformed tumour cell to produce a tumour of about one billion cells (a mass that weighs about 1 gram [0.04 ounce], the size at which it becomes clinically detectable), the cell must double its population 30 times.
A tumour nodule can grow to only a certain diameter (1 to 2 millimetres [0.04 to 0.08 inch]) before the cells are too distant from the nutrients and oxygen that they need to survive. For tumour expansion to occur, new capillaries (tiny blood vessels) must form within the tumour—a process called vascularization, or angiogenesis. Angiogenesis is a normal process in the body's replacement of damaged tissue, but it can also occur under abnormal conditions, as in tumour progression. At some point, after months or even years as a harmless cluster of cells, tumours may suddenly begin to generate blood vessels—apparently because they develop the ability to synthesize certain growth factors that stimulate the formation of vessels (a capability described below in Metastasis: the cellular view).
Once they have begun to grow, tumours are able to sustain their own growth in a semi-independent fashion. This results from growth factors produced by the tumour cells themselves (a self-stimulatory process called autocriny) and by the stromal cells (a process called paracriny).
Cancer cells can be distinguished from normal cells, and even from benign tumour cells, by microscopic examination. Differences in appearance include inconsistencies in size and shape and misshapen internal structures such as the nucleus, where genetic material is found. Genetic instability of the cell often gives rise to abnormal cells with giant nuclei that contain enormous amounts of deoxyribonucleic acid (DNA). When these highly abnormal cells divide by mitosis, the number of chromosomes formed is abnormally elevated, and the mitotic figures (the structures that help to coordinate the division of the chromosomes) are often distorted. Cancer cells also tend to be less well-differentiated than normal cells, a characteristic that is called anaplasia. When a malignant tumour no longer resembles the tissue of origin, it is said to be undifferentiated, or anaplastic.
Precancerous stage
Most tumours take many years to grow and form to the point where they produce clinical manifestations. Laryngeal cancer, for instance, appears only after several years of constant exposure to alcohol and tobacco smoke—a behaviour shared by many common tumours caused by environmental conditions. Careful studies of individuals with polyps of the colon (benign tumours of the inner lining of the large intestine) show that it takes three to five years for a new polyp to form and the same amount of time for the polyp to transform or progress into a carcinoma. Thus, when malignant tumours finally present with clinical manifestations, they are well into the last third of their life cycles.
In some instances it is known that certain abnormal cellular changes precede cancer. These alterations are collectively referred to as precancerous lesions. A number of terms, such as hyperplasia, dysplasia, and neoplasia, are used to describe precancerous lesions. For example, endometrial hyperplasia (increased cell growth in the endometrium, or inner lining of the uterus) often precedes, and may even set the stage for, cancer of the endometrium. Some clinical conditions are also known to be associated with an increased risk of carcinoma. Indeed, long-standing ulcerative colitis and leukoplakia of the oral cavity carry such an increase in risk that they are known as preneoplastic conditions for adenocarcinoma of the colon and squamous cell carcinoma of the mouth.
The noninvasive stage
Before tumours metastasize, or spread to other tissues of the body, they pass through a long period as noninvasive lesions. During this stage (the earliest stage in which cancer is recognized as such) the tumour remains in the anatomic site where it arose and does not invade beyond those confines. An example of such a lesion might be a carcinoma that has arisen from an epithelial cell lining the uterine cervix; as long as this carcinoma is confined to the mucosal lining and has not penetrated the basement membrane, which separates the lining from other tissue layers, it is known as a noninvasive tumour (or an in situ tumour). A tumour at this stage lacks its own network of blood vessels to supply nutrients and oxygen, and it has not sent cells into the circulatory system to give rise to new tumours. It also is usually asymptomatic—an unfortunate circumstance, because in situ tumours are curable.
Invasion and dissemination
In the next stage of tumour progression, a solid tumour invades nearby tissues by breaching the basement membrane. The basement membrane, or basal lamina, is a sheet of proteins and other substances to which epithelial cells adhere and that forms a barrier between tissues. Once tumours are able to break through this membrane, cancerous cells not only invade surrounding tissue substances but also enter the bloodstream—often via a lymphatic vessel, which discharges its contents into the blood. Tumour cells that have invaded a lymphatic vessel often become trapped in lymph nodes, whereas cells that gain access to blood vessels are disseminated to various parts of the body such as the bones, lungs, and brain. At such distant sites cancer cells form secondary tumours, or metastases. This ability to metastasize is what makes cancer such a lethal disease. The primary tumour (that is, the original tumour growing at the site of origin) can be controlled by many available therapies, but it is the disseminated disease that eventually proves fatal to the host.
Metastasis: the cellular view
In order to disseminate throughout the body, the cells of a solid tumour must be able to accomplish the following tasks. They must detach from neighbouring cells, break through supporting membranes, burrow through other tissues until they reach a lymphatic or blood vessel, and then migrate through the lining of that vessel. Next, individual cells or clumps of cells must enter the circulatory system for transport throughout the body. If they survive the journey through lymphatic vessels, veins, and arteries, they will eventually lodge in a capillary of another organ, where they may begin to multiply and form a secondary tumour.
Laboratory researchers have intensively studied this process in the hope that insight into the mechanisms of metastasis will provide ways to devise effective therapies. Each step has been individualized and studied, and mechanisms have been elucidated at the cellular and even the molecular level. Several of these mechanisms are described in this section.
Angiogenesis
As is mentioned above in Tumour progression: the clinical view, the formation of capillaries (a process known as angiogenesis) is an important step that a tumour undergoes in its transition from a small harmless mass of cells to a life-threatening malignant tumour. When they first arise in healthy tissue, tumour cells are not able to stimulate capillary development. At some point in their development, however, they call on proteins that stimulate angiogenesis, and they also develop the ability themselves to synthesize proteins with this capacity. One of these proteins is known as vascular endothelial growth factor (VEGF). VEGF induces endothelial cells (the building blocks of capillaries) to penetrate a tumour nodule and begin the process of capillary development. As the endothelial cells divide, they in turn secrete growth factors that stimulate the growth or motility of tumour cells. Thus, endothelial cells and tumour cells mutually stimulate each other.
Cancer cells also produce another type of protein that inhibits the growth of blood vessels. It seems, therefore, that a balance between angiogenesis inhibitors and angiogenesis stimulators determines whether the tumour begins capillary development. Evidence suggests that angiogenesis begins when cells decrease their production of the inhibiting proteins. Angiogenesis inhibitors are seen as promising therapeutic agents (see Diagnosis and treatment of cancer: Angiogenesis inhibitors).
Microinvasion
The process of invasion begins when one cancer cell detaches itself from the mass of tumour cells. Normally, cells are cohesive and stick to one another by a series of specialized molecules. An important early step in cancer invasion appears to be the loss of this property, known as cellular adhesion. In many epithelial tumours it has been shown that cell-adhesion molecules such as E-cadherin, which helps to keep cells in place, are in short supply.
Another type of adhesion that keeps cells in place is their attachment to the extracellular matrix, the network of substances secreted by cells and found between them that helps to provide structure in tissues. Normally, if a cell is unable to attach to the extracellular matrix, it dies through induction of the cell suicide program known as apoptosis. Cancer cells, however, develop a means to avoid death in this situation.
In order to gain access to a blood or lymphatic channel, cancer cells must move through the extracellular matrix and penetrate the basement membrane of the vessel. To do this, they must be able to forge a path through tissues, a task they perform with the aid of enzymes that digest the extracellular matrix. The cell either synthesizes these proteins or stimulates cells in the matrix to do so. The breakdown of the extracellular matrix not only creates a path of least resistance through which cancer cells can migrate but also gives rise to many biologically active molecules—some that promote angiogenesis and others that attract additional cells to the site.
Dissemination
Once in the bloodstream, tumour cells are disseminated to regions throughout the body. Eventually these cells lodge in capillaries of other organs and exit into those organs, where they grow and establish new metastases.
Not all the cancer cells within a malignant tumour are able to spread. Although all the cells in a tumour derive from a single cell, successive divisions give rise to a heterogeneous group of cancer cells, only some of which develop the genetic alterations that allow the cell to seed other tissues. Of those cells that are able to break away from the parent tumour and enter the circulation, probably less than 1 in 10,000 actually ends up creating a new tumour at a distant site.
Although the location and nature of the primary tumour determine the patterns of dissemination, many tumours spread preferentially to certain sites. This situation can be explained in part by the architecture of the circulatory system and the natural routes of blood flow. Circulating cancer cells often establish metastases “downstream” from their originating organ. For example, because the lungs are usually the first organ through which the blood flows after leaving most organs, they are the most common site of metastasis.
But circulation alone does not explain all cases of preferential spread. Clinical evidence suggests that a homing mechanism is responsible for some unlikely metastatic deposits. For example, prostate and breast cancers often disseminate first to the bone, and lung cancer often seeds new tumours in the adrenal glands. This homing phenomenon may be related to tumour cell recognition of specific “exit sites” from the circulation or to awareness of a particularly favourable—or forbidding— “soil” of another tissue. This may occur because of an affinity that exists between receptor proteins on the surface of cancer cells and molecules that are abundant in the extracellular matrix of specific tissues.
Because metastasis is such a biologically complex phenomenon, it is unlikely that a single genetic defect brings it about. It seems more reasonable to predict that a number of aberrant genes contribute to metastasis. Attempts to discover what genes are involved are ongoing and, it is hoped, will lead to new therapeutic approaches that halt tumour spread.
Effects of tumours on the individual
Most tumours require many years to form and grow to the point where they produce clinical manifestations. The signs and symptoms of benign or malignant tumours result for the most part from the local effects of either the primary tumour or its metastases. In some cases the primary tumour and the secondary metastases do not progress at the same pace, and in such an instance the primary tumour may manifest itself while the metastases do not cause symptoms and, as a result, go undetected for years.
In addition to local effects, malignant neoplasms produce systemic effects such as body wasting (cachexia) and a variety of clinical manifestations known as paraneoplastic syndromes. Both local and systemic effects are described in this section.
Local effects of tumour growth
Benign and malignant tumours produce a number of effects in an individual that vary depending on the location of the tumour, the tumour's functional activity, and any acute events that occur as the tumour mass grows and evolves. Metastatic tumours (those that result from the spread of the primary tumour) can produce the same consequences. A tumour affects normal bodily functions by compressing, invading, and destroying normal tissues and also by producing substances that circulate in the bloodstream.
Effects of location
The location of the tumour will determine how fast it manifests itself. Tumours arising in the deep soft tissues of the retroperitoneal space (the area next to the kidney) can grow very large before they produce discomfort. On the other hand, a relatively small tumour in the lungs can produce partial obstruction of secondary airways and cause pneumonia, which can draw attention to the tumour at an early stage.
The expansive growth of benign neoplasms or the more destructive growth of malignant tumours may erode natural surfaces and lead to the development of ulcers and bleeding and create conditions that favour infection. Tumours of the colon are indicated when small quantities of blood are found in the stools through an occult blood test.
Effects of functional activity
When abnormal tissue is growing in the midst of an organ, it is likely to interfere with the organ's function. Metastases growing in the adrenal gland, for instance, eventually can destroy the gland and produce adrenal insufficiency (a condition called Addison disease). Sometimes the clinical manifestations of a tumour result from a malfunction in the tumour cell itself. This is commonly seen in tumours of endocrine glands, whose cells produce excessive amounts of hormones. For example, benign tumours of the parathyroid gland (called parathyroid adenomas) oversecrete parathormone, which causes calcium levels in the blood to rise. Symptoms such as muscle weakness, fatigue, anorexia, nausea, and constipation are caused by the excess calcium levels.
Effects of acute events
In the life of a tumour, acute accidents can produce dramatic symptoms. For example, ovarian cysts can rupture and produce immediate and severe abdominal discomfort. Tumours growing freely in a cavity can become twisted and cut off the blood supply to the tumour. This interruption of blood flow can cause tissue death (infarction), which may result in internal bleeding and cause intense pain for the individual.
Systemic effects of malignant tumours
About 10 percent of persons with cancer have signs and symptoms that are not directly related to the location of a tumour or its metastases. Effects that appear at a distance from the tumour are called paraneoplastic syndromes. Such symptoms may be the first manifestation of a small tumour and thus may allow early detection and treatment of the disease. It is important that these symptoms not be confused with symptoms caused by advanced metastatic disease, as misdiagnosis can lead to inappropriate therapy.
Among the most dramatic paraneoplastic syndromes are those mediated by abnormal hormone production. For example, small-cell carcinomas of the lung can produce excessive amounts of adrenocortical-stimulating hormone. The hormone is circulated in the bloodstream and acts at a distance from the tumour, stimulating the adrenal glands to oversecrete corticosteroids which in turn produces Cushing syndrome—characterized by such symptoms as muscle weakness, hypertension, and high levels of glucose in the blood.
A common systemic effect of malignant tumours, particularly at advanced stages of growth, is body wasting (cachexia), which may appear with loss of appetite (anorexia) and weight loss. It is likely that a chemical mediator called tumour necrosis factor-alpha is one of the multiple molecules that bring about wasting effects. This factor is produced by immune cells called macrophages and sometimes is secreted by tumour cells.
Another common paraneoplastic manifestation is an increase in the clotting ability of the blood (hypercoagulability). A number of abnormalities can result from the hypercoagulable state, including migratory thrombophlebitis, a recurrent inflammation and thrombosis of the veins.
Many paraneoplastic syndromes that affect nervous and muscle functions are thought to be caused by autoimmune reactions that damage healthy tissue. Such a reaction occurs when the immune system produces antibodies that react to an antigen (e.g., a protein) produced by and found on the surface of the tumour cell. If this tumour antigen closely resembles an antigen normally found on the surface of neurons or muscle cells, the antibodies can cross react with these healthy cells, causing tissue damage.
The immune response to tumours
Immune surveillance
The autoimmune reaction described above is a negative effect of the immune response to cancer cells, but it does indicate that the body can mount a protective response to cancer. The immune system can identify and destroy emerging cancer cells because it recognizes abnormal antigens on the cell surface as “nonself,” or foreign. Because foreign substances are usually dangerous to the body, the immune system is programmed to destroy them.
This constant monitoring of the body for small tumours is known as immune surveillance. The process is known to operate in the rejection of tumour cells in persons with hereditary nonpolyposis colon cancer, also called Lynch syndrome. These individuals inherit a faulty DNA mismatch repair system and as a consequence produce many mutant proteins (see the section Causes of cancer: DNA repair defects). When these mutant proteins appear on the surface of tumour cells, they are recognized as foreign and rejected. Tumours that do emerge are those that have managed to evade the body's immune surveillance system.
Additional evidence for the role of immune mechanisms in cancer prevention is provided by individuals with damaged immune systems—for instance, persons born with immune deficiencies, people whose immune systems have been suppressed with chemicals to avoid rejection of transplanted organs, and individuals with acquired immunodeficiency syndrome (AIDS). These people are at greater risk of developing cancer—especially malignant lymphoma, a tumour of the lymphocytes (one of the major cellular components of the immune system). The types of lymphomas that develop are related to infection with the Epstein-Barr virus and human T-cell leukemia viruses. An increase in the most common forms of cancer—e.g., lung, breast, and colon—is not observed in immune-deficient patients.
Tumour antigens
The immune system responds to two general types of tumour antigens: tumour-specific antigens, which are unique to tumour cells, and tumour-associated antigens, which appear on both normal cells and cancer cells.
Tumour-specific antigens
Tumour-specific antigens represent fragments of novel proteins that are presented at the cell surface bound to the major histocompatibility complex class I molecules. In this form they are recognized by T lymphocytes (T cells) and eliminated. The novel peptides are derived from mutated proteins or from production of a protein that is not expressed in normal cells.
The first tumour found to carry a tumour-specific antigen was a malignant melanoma. The fact that melanomas occasionally undergo “spontaneous” regression in some individuals indicates that the immune response can be effective at eliminating these tumour cells.
Tumour-associated antigens
Tumour-associated antigens on tumour cells are not qualitatively different in structure from antigens found on normal cells, but they are present in significantly greater amounts. Because of their abundance, they are often shed into the bloodstream. Elevated levels of these antigens can be used as tumour markers—that is, indicators of a tumour.
Some tumour-associated antigens are normally produced by developing cells of the fetus or embryo but either are no longer produced by an adult or are produced only in small amounts. One such antigen is called the carcinoembryonic antigen (CEA). Elevated levels of CEA are found primarily in persons with cancers of the gastrointestinal tract and also in some patients with breast, lung, ovarian, pancreatic, and stomach cancers. (For information on the therapeutic applications of tumour antigens, see the section Diagnosis and treatment of cancer: Immunotherapy.)
Diagnosis and treatment of cancer
Greater insight into the causes and mechanisms of cancer has led to better ways to diagnose and treat the many forms of this disease. First of all, advances in detection have improved the ability to discover cancers earlier and to diagnose them more accurately than was the case only a few years ago. (Indeed, some tests can identify precancerous tumours before symptoms appear and thus can be used to prevent cancers from developing.) In addition, improvements in conventional cancer treatments can cure many cases of cancer, and new therapeutic strategies show promise of being even more effective in thwarting the disease. This section reviews both conventional and innovative methods of diagnosing and treating cancer.
Diagnostic procedures
In order for cancer to be diagnosed as early as possible, an individual should be aware of symptoms that may be related to the disease. The American Cancer Society lists seven basic warning signs of cancer: unusual bleeding or discharge, persistent hoarseness or cough, changes in bowel or bladder habits, a persistent thickening or lump, a sore that does not heal within two weeks, indigestion or trouble swallowing, and a change in the appearance of a mole or wart.
The physician evaluating a person with any of these symptoms comes up with a diagnostic workup to determine whether a tumour is present and, if so, whether the growth is benign or malignant. The diagnostic methods employed depend on the type and location of the suspected tumour.
The standard diagnostic workup begins with a detailed clinical history of the person. A complete physical examination, including laboratory tests such as a complete blood count and a urinalysis, is made. Diagnostic imaging using X rays, ultrasound, computed tomography (CT) scans, or magnetic resonance imaging (MRI) may be essential, and radioisotopes can be used to visualize certain organs or regions of the body. If necessary, the physician can use an endoscope to inspect the internal cavities and hollow viscera. An endoscope is an optical instrument that makes it possible not only to observe the appearance of the internal linings but also to perform a biopsy, a procedure used to procure a tissue sample from a lesion for evaluation.
Biopsy
Biopsies, the most definitive diagnostic tests for cancer, can be performed in the physician's office or in the operating room. There are different techniques. In excisional biopsy, the entire tumour is removed. This procedure is carried out when the mass is small enough to be removed completely without adverse consequences. Incisional biopsies, which remove only a piece of a tumour, are done if the mass is large. Biopsies obtained with visual control of an endoscope consist of small fragments of tissue, usually no larger than 5 millimetres (0.2 inch) long. Needle biopsy involves the removal of a core of tissue from a tumour mass with a specially designed needle often under imaging guidance. Alternatively, the needle can be stereotactically guided to a previously localized lesion. This type of biopsy yields a tissue core or cylinder and is frequently used for the diagnosis of breast masses and biopsies of brain lesions.
Another type of biopsy, called fine-needle aspiration biopsy, yields cells rather than a tissue sample, so that the pathologist is able to assess only cellular features and not the architectural characteristics of the tumour tissue. Nevertheless, fine-needle aspiration has many positive qualities. It is relatively painless and free of complications. In many instances it is a worthwhile adjunct to the diagnosis. Unlike a tissue sample, which may take two days to examine, a sample obtained by fine-needle aspiration can be examined and interpreted within a day or even in a matter of hours.
When it is necessary to identify the nature of a mass during a surgical operation, a biopsy can be performed and the tissue sample frozen for microscopic examination. Following this quick method, samples of tissue are frozen and then sliced into thin sections that are stained and examined under the microscope. Frozen sections are also used to assess whether the tumour has been completely excised. This is done by taking tissue samples from areas adjacent to the tumour to confirm that all diseased cells have been removed. In general, the rate of diagnostic accuracy of frozen sections is 95 to 97 percent.
Biopsy interpretation is a highly accurate technique that is supplemented with special methods of examination. Tissue sections can be viewed with an electron microscope, or they can be stained, using an immunohistochemical approach that uses antibodies directed against tumour-associated antigens. Molecular biological techniques can be employed to detect mutations in proto-oncogenes and tumour suppressor genes, and cytogenetic tests can be performed on tissue samples to analyze the chromosome content of the cells.
Evaluation of tumours
Grading and staging
A major factor governing the choice of therapy is the grade and stage of the tumour. In many cases grading and staging schemes can help to predict the behaviour of a tumour and thereby determine the most appropriate approach to treatment.
Grading schemes classify tumours according to the structure, composition, and function of tumour tissue—in clinical terms, the histological features of the tumour. The histological grade of a tumour refers to the degree of tissue differentiation or to an ensemble of tissue features that have been found to be a good predictor of the aggressiveness of the tumour. Most grading schemes classify a type of cancer into three or four levels of increasing malignancy.
Staging protocols, which are independent of grading schemes, are employed to describe the size and dissemination of the tumour, both in the organ in which it arose and beyond it. For every type of tumour, a series of tests and procedures are codified in order to assess how far the tumour has extended in the patient's body. Each tumour staging system is complemented by a grading method.
An internationally standardized classification system is the TNM staging system, put forth by the Union Internationale Contre le Cancer and the American Joint Committee on Cancer. In this system T refers to the size of the primary tumour, N to the presence and extent of lymph node metastases, and M to the presence of distant metastases.
Molecular evaluation
Besides stage and grade, other prognostic factors exist for many types of cancer. Cancers can be defined not only by their appearance but also by the pattern of altered gene activity. Definition of this altered pattern by molecular tests can help to predict the rapidity of growth of the tumour, its tendency to spread, and its response to therapies.
Molecular procedures, when integrated with conventional grading and staging procedures, are likely to improve significantly the present systems of prognostication. Some are based on detecting and measuring the level of substances produced by the tumour. These substances, called tumour markers, also can aid in monitoring an individual who has received treatment for cancer to determine whether the tumour has returned. A rising level of a tumour marker in the blood will in general indicate the regrowth of the tumour. Diagnostically useful tumour markers include carcinoembryonic antigen (CEA), which is an indicator of carcinomas of the gastrointestinal tract, lung, and breast; CA 125, which is produced by ovarian cancers; CA 19-9, which indicates pancreatic or gastrointestinal cancers; and alpha-fetoprotein and chorionic gonadotropin, which can indicate testicular cancer.
Tumour markers also can be used to estimate the proportion of cells in a tumour that are actively growing. This approach has prognostic significance because tumours with a high proportion of dividing cells tend to be more aggressive.
It is often the case that the more abnormal the DNA content per cell, the more difficult the tumour will be to control. It is possible to refine the prognosis of a tumour by examining the specific genetic alterations found in the cells of the tumour. For example, neuroblastoma cells that contain amplified amounts of the N-MYC gene indicate a worse prognosis for the individual than do cells from identical tumours that have the normal genetic complement of N-MYC (see the section Causes of cancer: Gene amplification).
A sensitive molecular technique called the polymerase chain reaction (PCR) makes it possible to detect mutations that identify certain tumours when only a small number of cancer cells are present. For example, in individuals with leukemia who have received bone marrow transplants, a PCR assay can discover very low levels of residual malignant cells in the circulation and thus provide a sensitive indicator of the success of the therapy.
Therapeutic strategies
Once a diagnosis of cancer has been established, a plan for treatment is needed. A therapeutic strategy is best achieved by a multidisciplinary team of physicians that includes surgeons, medical and radiation oncologists, diagnostic radiologists, pathologists, and—depending on the operations planned—plastic and reconstructive surgeons or physical rehabilitation specialists.
Therapeutic strategies must be tested in experimental trials using specific scientific methods and standards before they are proven effective. The largest risk in using unproven approaches is that they may cause a delay in treatment with a proven method.
Conventional therapies
Surgery, radiation, and chemotherapy alone or in combination are the most common methods used to treat cancer. The specific treatment will vary depending on the kind of cancer, the extent of the disease, its rate of progression, the condition of the patient, and the response to therapy.
Surgery
Surgery is the oldest form of cancer therapy and was until recently the only method that could actually cure cancer. It is still the principal cure.
Although new advances in surgical techniques have allowed for the successful removal of many cancers, the development of other treatment strategies has reduced the extent of surgical intervention in treating some cancers. And in spite of new surgical techniques, the ability of surgery to control cancer is limited by the fact that, at the time of surgical intervention, two-thirds of cancer patients have tumours that have spread beyond the primary site.
In planning the definitive treatment of an individual with a solid tumour, the surgical oncologist confronts several challenges. One major concern to be addressed is whether the patient can be cured by local treatment alone and, if so, which type of operation will provide the best balance between cure and impact on the quality of life. With many tumours the magnitude of the resection is modified by adjuvant therapies. Therapy also has improved by combining surgery with other types of treatment. For example, survival rates of childhood rhabdomyosarcoma (a type of muscle tumour) were only 20 percent when radical surgery alone was used. However, when adjuvant radiation therapy and later chemotherapy were used in combination with surgery, cure rates rose to 80 percent.
Although surgery often is intended to be curative, it may sometimes be used to assuage pain or dysfunction. This type of surgery, called palliative surgery, can remove an intestinal obstruction or remove masses that are causing pain or disfigurement.
Certain conditions associated with a high incidence of cancer can be prevented by prophylactic surgery. One such condition is cryptorchidism, a developmental defect in which the testes do not descend into the scrotum (which creates a risk of developing testicular cancer). A surgical procedure called orchiopexy can correct this defect and thereby prevent malignant disease from occurring. Diseases including multiple polyposis of the colon and longstanding severe ulcerative colitis are associated with a high risk for colon cancer, and they can be treated by partial or complete removal of the colon. Individuals with multiple endocrine neoplasia, who are at risk of developing medullary cancer of the thyroid, likewise can be treated by having the thyroid removed.
Radiation therapy
Radiation therapy is the use of ionizing radiation—X rays, gamma rays, or subatomic particles such as neutrons—to destroy cancer cells. Approximately 50 percent of all individuals diagnosed with cancer receive radiation therapy. Only surgery is more commonly used.
Cells are destroyed by radiation either because they sustain so much genetic damage that they cannot replicate or because the radiation induces apoptosis (or programmed cell death). Cancer cells are more sensitive to radiation than are healthy cells because they are continuously proliferating. This factor renders them less able to recover from radiation damage than normal cells, which are not always reproducing.
Different ranges, or voltages, of radiation are used in clinical practice. The lowest range is called superficial radiation; the medium range is called orthovoltage; and the high range is called supervoltage. Two techniques are used to deliver radiation therapy in the clinic: brachytherapy and teletherapy. In brachytherapy, also called internal radiation therapy, the source of radiation is placed directly into the tumour or within a nearby body cavity. Some of the substances used are radioactive isotopes of iridium, cesium, gold, and iodine. The devices used to contain the radioactive substances are diverse in form (e.g., tubes, needles, grains, and wires). Sometimes the radioactive source is delivered to the tumour through tubes and then withdrawn—an approach called remote brachytherapy. Teletherapy, or external radiation therapy, uses a device such as a clinical linear accelerator to deliver orthovoltage or supervoltage radiation at a distance from the patient. The energy beam can be modified to adapt the dose distribution to the volume of tissue being irradiated.
Once the decision has been made to use external beam radiation, a series of pretreatment procedures are performed. First, the precise location of the tumour is identified by means of magnetic resonance imaging (MRI). Next, the appropriate energy level is selected, and the beam distribution and dose distribution are carefully determined so as to maximize the therapeutic effect and minimize damage to healthy tissues. Precise irradiation requires devices (casts) that carefully position the patient. Sometimes markings are used to position and delimit the fields. This is necessary because radiation is administered in repeated small doses, called fractions. Fractionation minimizes complications and, when given at equal doses, allows for a more effective cure. For some tumours—including cancer of the uterine cervix, larynx, breast, and prostate, as well as Hodgkin disease and seminoma (a type of testicular cancer)—curative doses of radiation can be applied without causing serious damage to surrounding tissues.
The undesirable effects of radiation therapy are divided into acute and late effects. Acute effects occur in rapidly renewing tissues, such as the linings of the oral cavity, pharynx, intestine, urinary bladder, and vagina. Late effects, which are related to the total dose of radiation received, include scar formation (fibrosis), tissue loss, and creation of abnormal openings (fistulae). Secondary effects can be minimized by internal radiation, a form of therapy that delivers a high dose of radiation to the tumour with less exposure to normal tissues.
Radiation therapy is often combined with surgery. Although surgery is most useful in removing a localized tumour, it may fail to remove cells that have spread beyond the margins of the surgical procedure. Conversely, radiation therapy is most effective at eradicating undetected disease at the periphery of the tumour and least effective in killing cells at the centre of large tumours. Thus, in certain situations—such as the limited excision of a breast tumour (lumpectomy) followed by radiation therapy—the weaknesses of each therapy are offset by the strengths of the other.
Chemotherapy
Chemotherapy is the administration of chemical compounds, or drugs, to eliminate cancer cells. Chemicals destroy cancer cells by preventing them from multiplying. Unlike surgery or radiation therapy, which cannot treat widespread metastases, anticancer drugs can disperse throughout the body via the bloodstream and attack tumour cells wherever they are growing—with the exception of a few sites in the body known as “sanctuaries,” areas where the drug does not actually reach the tumour cells.
The first chemotherapeutic agent used against cancer was a nitrogen-mustard compound employed in the 1940s to treat Hodgkin disease and other lymphomas. There are now about 100 different drugs used in the treatment of cancer. They are classified by their structure and function as alkylating agents, antimetabolites, natural products, hormones, and miscellaneous agents. Chemotherapeutic agents are used in four situations: (1) They are chosen in some cases as the primary treatment for individuals with a localized cancer. (2) They are administered as the primary therapy for individuals with advanced cancer for which there is no other alternative therapy. (3) They are used as an adjunct therapy to radiation or surgery. (4) They are administered directly to sanctuaries that are not reached by the bloodstream or to specific regions of the body most affected by the disease.
With some notable exceptions—such as Burkitt lymphoma and choriocarcinoma—cancer cannot be eradicated with only a single chemotherapeutic agent. In order to produce a lasting clinical response, a combination of drugs is required. Combination chemotherapy was first used to treat leukemia and lymphoma. After considerable success in treating these malignancies, combination chemotherapy was extended to solid tumours.
Unfortunately, cancer cells can develop resistance to chemotherapy, just as bacteria can become resistant to antibiotics. One explanation for the development of drug resistance (and resistance to radiation as well) is that apoptosis (or programmed cell death) cannot be induced in certain cancer cells. It is known that both chemotherapy and radiation therapy kill cells by inducing apoptosis, essentially making the cell trigger the program of cell death rather than succumb to the action of the chemical itself.
The side effects of chemotherapy vary greatly among individuals and among drug combinations. Side effects arise because many chemotherapeutic agents kill healthy cells as well as cancer cells. Nausea, vomiting, diarrhea, hair loss, anemia, loss of ability to fight infection, and a greater propensity to bleed may be caused by chemotherapy. Many side effects can be minimized or palliated and are of limited duration. No relationship exists between the efficacy of a drug on a tumour and the presence or absence of side effects.
Bone marrow transplantation
One of the most life-threatening effects of high doses of chemotherapy—and of radiation as well—is damage that can be done to bone marrow. Found within the cavities of bones, marrow is rich in blood-forming (hematopoietic) stem cells, which develop into oxygen-bearing red blood cells, infection-fighting white blood cells, and clot-forming platelets. Chemotherapy can decrease the number of white blood cells and reduce the platelet count, which in turn increases susceptibility to infection and can cause bleeding. Loss of red blood cells also can occur, resulting in anemia.
One way to offset these effects is through bone marrow transplantation. Strictly speaking, bone marrow transplantation is not a therapy for most forms of cancer (two exceptions being leukemia and lymphoma). Rather, it is a means of strengthening an individual whose blood-making system has been weakened by aggressive cancer treatments.
There are two common approaches to marrow transplantation: autologous and allogeneic transplants. (The phrase stem cell therapy is more accurate than bone marrow transplantation, since it has become common whenever possible to collect stem cells from the blood.) An autologous transplant involves the harvesting and storage of the patient's own stem cells before therapy. After the patient has received high levels of chemotherapy or radiation to destroy the cancer cells, the stem cells are injected into the bloodstream to speed recovery of the bone marrow. If an individual's marrow is diseased—from leukemia, for example—a person with a matching tissue type is found to donate stem cells. This type of transplant, called an allogeneic transplant, carries the risk of mismatch between tissues—a situation that can stimulate immune cells of the host to react with the donated cells and cause a life-threatening condition called graft-versus-host disease. Because of the danger of this complication, autologous transplants are more commonly performed. In these cases the patient's stem cells can be removed, purged of cancer cells, and then returned.
Biological therapies
Biological therapy has emerged as an important “fourth” accepted method as a result of gains made in understanding the immune defenses against cancer. Progress in biotechnology has provided necessary quantities of biochemical molecules to support this therapy.
Angiogenesis inhibitors
Since the progression of tumours requires the development of capillaries (a process known as angiogenesis) that supply tumour cells with oxygen and nutrients, interfering with this essential step is a promising therapeutic approach. Antiangiogenic drugs have been shown in animal studies to shrink tumours by destroying the capillaries that surround them and by preventing the production of new vessels. In combination with conventional therapy, they might be useful in the treatment of cancer. They remain an object of intensive research.
Immunotherapy
Tumour-associated antigens are present on tumour cells, but they also are found on the surface of normal cells; in addition, these antigens are not specific to a certain type of tumour but are seen in a variety of cancers. Despite the lack of tumour specificity, some tumour-associated antigens can serve as targets for attack by components of the immune system. For instance, antibodies can be produced that recognize a specific tumour antigen, and these antibodies can be linked to a variety of compounds—such as chemotherapeutic drugs and radioactive isotopes—that damage cancer cells. In this way the antibody serves as a sort of “magic bullet” that delivers the therapeutic agent directly to the tumour cell. In other cases a chemotherapeutic agent attached to an antibody destroys cancer cells by interacting with receptors on their surfaces that trigger apoptosis.
Another immunologic approach to treating cancer is the so-called tumour vaccine. The object of a cancer vaccine is to stimulate components of the immune system, such as T cells, to recognize, attack, and destroy cancer cells. Tumour vaccines have been created by using a number of different substances, including tumour antigens and inactivated cancer cells.
Tumour-associated antigens also can be used as tumour markers. Because elevated levels of tumour-associated antigens indicate that the presence of a tumour is likely, they remain a useful tool either in screening for the recurrence of previously treated cancers or in preventive screening. For example, prostate-specific antigen (PSA) is used to screen for carcinoma of the prostate.
Other biological response modifiers that have been developed include interferon, tumour necrosis factor, and various interleukins. Interleukin-2, for example, stimulates the growth of a wide range of antigen-fighting cells, including several kinds that can kill cancer cells.
Gene therapy
Knowledge about the genetic defects that lead to cancer suggests that cancer can be treated by fixing these altered genes. One strategy is to replace a defective gene with its normal counterpart, using methods of recombinant DNA technology. Researchers are exploring methods that can insert genes into tumour cells.
Strategies for cancer prevention
As scientific evidence points to specific agents as the causes of cancer, cancer death rates might be reduced through avoidance of these factors. One such preventative action is to avoid smoking tobacco. In the case of certain viruses that are linked to cancer—for example, hepatitis B virus, which is linked to liver cancer—vaccination campaigns may reduce cancer incidence. Certain modifications of diet—such as eating more fruits, vegetables, and legumes (e.g., peas and beans) and less red meat and saturated fats—can increase the odds of avoiding cancer. International epidemiological and laboratory studies provide strong evidence that a high intake of dietary fat is associated with an increased incidence of breast, colon, rectal, and prostate cancer.
Chemoprevention
Chemoprevention is the use of chemical compounds to intervene in the early precancerous stages of carcinogenesis (the development of cancer) and thereby reverse tumour formation. Many chemopreventive agents, both natural and synthetic, have been identified. Some of the most promising compounds are found in vegetables and fruits. For example, dithiothiones are potential chemopreventive agents that naturally occur in broccoli and cauliflower. A number of anticancer drugs under study also show promise in preventing cancer. These include antiestrogen drugs such as tamoxifen, which has been shown to reduce the incidence of breast cancer.
Individuals with precancerous lesions and those with a previous cancer who are at risk for a second tumour are most often included in chemoprevention research trials.
Screening and early detection
It is possible to screen asymptomatic individuals for various types of cancer, such as breast, cervical, prostate, colorectal, and skin cancers. In these instances tests can detect a precancerous condition or a tumour in an early stage so that it can be removed. For example, self-examination of the breasts and yearly mammograms contribute significantly to the early detection of tumours and the success of therapy. Self-exams are also useful in detecting early stages of testicular cancer. In other cases, however, such as when a detectable preclinical phase of a cancer is not known or there is no effective treatment for the cancer, screening programs may not be beneficial.
Causes of cancer
The billions of cells that make up a tumour are descended from a single cell that has found a way to escape the normal controls of its growth. This loss of control is caused by damage of the genetic material in the cell, specifically the long, coiled chains of deoxyribonucleic acid (DNA) found in the chromosomes. Such damage can arise during cell division, be induced by environmental agents, or be inherited. Regardless of how the damage is caused, genetic changes and the abnormal growth pattern that they promote are passed on to a cell's progeny (its daughter cells) as the cell divides.
Still, a single damaging genetic event is not enough to convert a healthy cell to a cancer cell. Evidence shows that several accidents must occur to the DNA of one cell for it to become cancerous. In many cases this is a slow process that takes years.
This section begins by explaining the genetic accidents that can give rise to cancer. It then describes various agents in the environment that can induce these changes. Finally, the inherited genetic alterations that predispose an individual to cancer are discussed.
The molecular basis of cancer
Cells are constantly faced with the decision of whether to proliferate (through cell division), differentiate (by expressing specialized properties that distinguish one tissue or organ from the others), or die. Involved in these decisions are a small number of genes—about 100 of the tens of thousands of genes that make up the human genome. Genes are encoded in the DNA molecules of the chromosomes, which are found in the cell nucleus. A gene can be thought of as a recipe that the cell follows to make a protein, each gene providing directions for a different protein.
The genes that regulate the growth of cells can be divided into two categories: proto-oncogenes, which encourage cell growth, and tumour suppressor genes, which inhibit it. Many of the agents known to cause cancer (chemicals, viruses, and radiation) exert their effects by inducing changes in these genes or by interfering with the function of the proteins encoded by these genes. Mutations in proto-oncogenes tend to overstimulate cell growth, keeping the cell active when it should be at rest, whereas mutations in tumour suppressor genes eliminate necessary brakes on cell growth, also keeping the cell constantly active.
The normal cell is able to repair such genetic damage through its DNA repair mechanisms, such as the so-called mismatch repair genes, whose normal function is to identify and repair defective DNA segments that arise in the normal course of a cell's life. However, if the cell's repair mechanisms are faulty, mutations will accumulate, and genetic damage that has not been repaired will be reproduced and passed to all daughter cells whenever the cell divides. In this way malfunctioning DNA repair machinery contributes to the genesis of some cancers.
When a normal cell senses that its DNA has been damaged, it will stop dividing until the damage has been repaired. But when the damage is massive, the cell may abandon any attempt at repair and instead activate a suicide program called apoptosis, or programmed cell death. The life of a cell can be prolonged for a number of reasons; for example, an excess of molecules that prevent the suicide program from occurring may be present, or the molecules that trigger the apoptotic process may be defective. Significant prolongation of a cell's life increases the chances that it will accumulate mutations in its DNA that transform the cell. Thus, the failure of a cell to die when it should is another factor that can contribute to carcinogenesis (the development of cancer).
Each of the cancer-causing genetic changes summarized above—mutated proto-oncogenes and tumour suppressor genes, defective DNA repair mechanisms, and failure to trigger apoptosis—is described in more detail below. Alternatively, the reader may proceed directly to the section Cancer-causing agents for a review of the most important carcinogens and their mechanisms of action.
Oncogenes
Retroviruses and the discovery of oncogenes
Although viruses play no role in most human cancers, a number of them do stimulate the growth of tumours in animals. Because of this, they have served as important laboratory tools in the elucidation of the genetics of cancer.
The viruses that have been most useful to research are the retroviruses. Unlike most organisms, whose genetic information is contained in molecules of DNA, the genes of retroviruses are encoded by molecules of RNA (ribonucleic acid). When retroviruses infect a cell, a viral enzyme called reverse transcriptase copies the RNA into DNA. The DNA molecule then integrates into the genome of the host cell to be replicated so that new viral progeny can be made.
Two types of cancer-causing, or transforming, retroviruses can be distinguished on the basis of the time interval between infection and tumour development: acutely transforming retroviruses, which produce tumours within weeks of infection, and slowly transforming retroviruses, which require months to elicit tumour growth. When acutely transforming retroviruses infect a cell, they are able to incorporate some of the host cell's genetic material into their own genome. Then, when the retrovirus infects another cell, it carries this new genetic material with it and integrates this tagalong material along with its own genome into the genome of the next cell. It was the discovery of this ability that led to the discovery of oncogenes.
Researchers had known since the early 20th century that infection with one type of acutely transforming retrovirus, called the Rous sarcoma virus, could transform normal cells into abnormally proliferating cells, but they did not know how this happened until 1970. In that year researchers working with mutant forms of Rous sarcoma virus—i.e., nontransforming forms of the virus that did not cause tumours—found that the transforming ability disappeared owing to the loss or inactivation of a gene, called src, that was active in transforming viruses. In this way, src was identified as the first cancer gene, called an oncogene (from Greek onkos, “mass” or “tumour”).
Researchers found that src was in fact not a viral gene but one that the retrovirus had picked up accidentally from a host cell during a previous infection. The src gene, then, was really a cellular oncogene, or proto-oncogene. Molecular hybridization studies demonstrated that the cellular version of src was very similar, but not identical, to the viral src gene. The cellular oncogene form of src was found to be an important regulator of cell growth that became altered when the virus removed it from the cellular genome. When inserted in another cell, the altered proto-oncogene became a cancer-causing oncogene, instructing the cell to divide more rapidly than it would normally
Another type of retrovirus found to cause tumour growth is the slowly transforming retrovirus. Unlike acutely transforming retroviruses, these retroviruses do not disrupt normal cellular functioning through insertion of a viral oncogene. Instead, they produce tumours by inserting their genomes into critical sites in the cellular genome—next to or within a proto-oncogene, for example—which thereby converts it into an oncogene. This mechanism, called insertional mutagenesis, can cause an oncogene to become overactive, or it can inactivate a tumour suppressor gene (see the section below, Tumour suppressor genes).
Proto-oncogenes and the cell cycle
A large number of oncogenes have been identified in retroviruses, and all have led to the discovery of proto-oncogenes that are integral to the control of cell growth. Proto-oncogenes control the growth and division of cells by coding for proteins that form a signaling “cascade.” This cascade relays messages from the exterior of the cell to the nucleus, where a molecular apparatus called the cell cycle clock resides. At the same time, tumour suppressor genes code for a similar cascade of inhibitory signals that also converge on the cell cycle clock. The cell cycle is a four-stage process in which the cell increases in size (G1 stage), copies its DNA (S stage), prepares to divide (G2 stage), and divides (M stage). On the basis of the stimulatory and inhibitory messages it receives, the clock “decides” whether the cell should enter the cell cycle and divide. If something goes wrong with the signaling cascades—say, if a stimulatory molecule is overproduced or an inhibitory molecule is inactivated—the clock's decision-making ability may be impaired. The cell has taken the first step toward becoming a tumour cell.
The proteins that play a role in stimulating cell division can be classified into four groups—growth factors, growth factor receptors, signal transducers, and nuclear regulatory proteins (transcription factors). For a stimulatory signal to reach the nucleus and “turn on” cell division, four main steps must occur. First, a growth factor must bind to its receptor on the cell membrane. Second, the receptor must become temporarily activated by this binding event. Third, this activation must stimulate a signal to be transmitted, or transduced, from the receptor at the cell surface to the nucleus within the cell. Finally, transcription factors within the nucleus must initiate the transcription of genes involved in cell proliferation. (Transcription is the process by which DNA is converted into RNA. Proteins are then made according to the RNA blueprint, and therefore transcription is crucial as an initial step in protein production.)
Any one of the four steps outlined above can be sabotaged by a defective proto-oncogene and lead to malignant transformation of the cell. A good example of this defect can be seen in the ras family of oncogenes. The ras oncogene has a single defect in its nucleotide sequence, and, as a result, there is a change of a single amino acid in the protein for which it encodes. The ras protein is important in the signal transduction pathway; mutant proteins encoded by a mutant ras gene constantly send activation signals along the cascade, even when not stimulated to do so. Overactive ras proteins are found in about 25 percent of all human cancers, including carcinomas of the pancreas, lung, and colon.
From proto-oncogenes to oncogenes
Although retroviruses can induce tumour development in animals, only a few instances are known of human proto-oncogenes being mutated into oncogenes by retroviral insertion. Nevertheless, various forms of genetic mutation and alteration can convert a human proto-oncogene into an oncogene. Three main mechanisms have been identified: chromosomal translocation, gene amplification, and point mutation.
Chromosomal translocation
Chromosomal translocation has been linked to several types of human leukemias and lymphomas. Through chromosomal translocation one segment of a chromosome breaks off and is joined to another chromosome. As a result of such an event, two separate genes can be fused. In some cases the newly created gene leads to tumour development. Such is the case with the so-called Philadelphia chromosome, the first translocation to be linked to a human cancer—chronic myelogenous leukemia. The Philadelphia chromosome is found in more than 90 percent of patients with chronic myelogenous leukemia. This well-known example of translocation involves the fusion of a proto-oncogene called c-ABL, which is located on chromosome 9, to a site on chromosome 22 known as a breakpoint cluster region (BCR). BCR and the c-ABL gene produce a hybrid oncogene, BCR-ABL, which produces a mutant protein that aberrantly regulates cellular proliferation. The exact mechanism by which the newly created BCR-ABL protein gives rise to leukemia is not yet understood.
Sometimes translocations do not generate a new gene but instead place an intact gene under the control of a regulatory element that normally acts on another gene. This situation occurs in about 75 percent of cases of Burkitt lymphoma. In the cells of patients with this cancer, a proto-oncogene called c-MYC is moved from its site on chromosome 8 to a site on chromosome 14. In its new location the c-MYC gene is positioned next to the switch signal, or promoter region, for the immunoglobulin G gene. As a result, the MYC protein encoded by the c-MYC gene is produced continuously.
Gene amplification
Gene amplification is another type of chromosomal abnormality exhibited by some human tumours. It involves an increase in the number of copies of a proto-oncogene, an aberration that also can result in excessive production of the protein encoded by the proto-oncogene. Amplification of the N-MYC proto-oncogene is seen in about 40 percent of cases of neuroblastoma, a tumour of the sympathetic nervous system that commonly occurs in children. The higher the copy number of the N-MYC gene, the more advanced the disease. Amplification of the proto-oncogene c-ERBB2 (HER2) is seen in some breast cancers.
Point mutation
Another mechanism by which a proto-oncogene can be transformed into an oncogene is point mutation. To understand what a point mutation is, it must first be explained that DNA molecules—and hence the genes found along their length—are composed of building blocks called nucleotide bases. A proto-oncogene may be converted into an oncogene through a single alteration of a nucleotide. This alteration may be the deletion of a base, the insertion of an extra base, or the substitution of one base for another. Point mutations also can be caused by radiation or chemicals that disrupt the DNA. However, regardless of the type or cause of such a mutation, it usually changes the amino acid sequence of the encoded protein and thus alters protein function.
A point mutation can increase protein function—as occurs with the ras family of proto-oncogenes—or it can interrupt protein synthesis so that little or no protein is made. Point mutations are common mechanisms of inactivation of tumour suppressor genes.
Tumour suppressor genes
Tumour suppressor genes, like proto-oncogenes, are involved in the normal regulation of cell growth; but unlike proto-oncogenes, which promote cell division and differentiation, tumour suppressors restrain them. If proto-oncogenes are the accelerators of cell growth, tumour suppressor genes are the brakes.
Just as the term oncogene is somewhat misleading because it suggests that the main function of the gene is to cause cancer, the name tumour suppressor gene wrongly suggests that the primary function of these genes is to stem tumour growth. This terminology has to do with the history of their discovery; loss of function of these genes was seen in practically all tumours, and restoration of their function inhibited tumour growth.
Unlike proto-oncogenes, which require that only one copy of the gene be mutated to disrupt gene function, both copies (or alleles) of a particular tumour suppressor gene must be altered to inactivate gene function. In many tumours one copy of a tumour suppressor gene is mutated, producing a gene product that cannot work properly, and the second copy is lost by allelic deletion (see the section above, From proto-oncogenes to oncogenes: Point mutation).
The RB and p53 genes
Two of the most studied tumour suppressor genes are RB and p53. The RB gene is associated with retinoblastoma, a cancer of the eye that affects 1 in every 20,000 infants. The gene also is associated with bone tumours (osteosarcomas) of children and cancers of the breast, prostate, lung, uterine cervix, and bladder in adults. The p53 gene, which is named for the molecular weight of its protein product (53 kilodaltons), is the most commonly mutated gene in tumours. Practically every person who inherits a mutated copy of a tumour suppressor gene will develop some form of cancer (see the section Inherited susceptibility to cancer).
Discovery of the first tumour suppressor gene
Studies of human hereditary cancers provided compelling evidence for the existence of tumour suppressor genes. In 1971 American researcher Alfred Knudson, Jr., focused on retinoblastoma, which occurs in two forms: a nonhereditary, or sporadic, form and a hereditary form that occurs much earlier in life. To explain the differences in tumour rates between these two forms, Knudson proposed a “two-hit hypothesis.” He postulated that in the inherited form of the disease, a child inherits one mutated RB allele from a parent. This single mutation, which is present in every cell, is not sufficient to stimulate tumour formation because the second copy of the RB allele, which is not mutated, functions normally. For a tumour to form, one random mutation must occur in the healthy RB allele of a retinal cell after conception. In contrast, in sporadic cases of retinoblastoma, a sequence of two inactivating events must occur after conception. Because it is much less likely that two random mutation events will occur in the same gene than that one random event will occur, the rate of occurrence of nonhereditary retinoblastoma is much lower than that of the inherited form.
Loss of function of the RB protein
The protein E2F is a transcription factor that binds to DNA to stimulate the synthesis of proteins necessary for cell division. When E2F is bound to the RB protein, however, it cannot bind to DNA. Thus, when functioning normally, the RB protein prevents a cell from dividing by binding to E2F. When RB is absent or inactivated, this restraint is lost, and E2F is constantly available to trigger cell division.
The p53 gene
The p53 protein was discovered in 1979. It resides in the nucleus, where it regulates cell proliferation and cell death. In particular, it prevents cells with damaged DNA from dividing or, when damage is too great, promotes apoptosis. Cells exposed to mutagens (chemicals or radiation capable of mutating the DNA) need time to repair any genetic damage they sustain so that they do not copy errors into the DNA of their daughter cells. When mutations occur, normal levels of the p53 protein rise, which slows the transition of the cell cycle from the G1 phase to the S phase. This extra time allows DNA repair mechanisms to effectively restore the DNA sequences to normalcy. The brakes on the cell cycle—high p53 levels—are then removed, and the cell proceeds to divide.
If there is a large amount of genetic damage, p53 triggers a series of biochemical reactions that cause the cell to self-destruct. Total functional inactivation of the p53 gene will cause genetic damage to accumulate in the cell and will also fail to set off apoptosis in severely injured cells.
Both radiation therapy and chemotherapy can kill tumour cells by stimulating apoptosis. Some tumours that have lost p53 function are more resistant to therapy because of the cells' diminished capacity to trigger cell death. (See the section Diagnosis and treatment of cancer: Therapeutic strategies.)
Inactivation of the p53 gene occurs through mutation of one allele and loss of the other accounts for 70 percent of cases of colon carcinoma, 30 to 50 percent of cases of breast cancer, and 50 percent of cases of lung cancer. In two other types of cancer, inactivation of the p53 gene occurs not through mutation and loss of the alleles but through binding of the p53 protein with another protein (called an antagonist) that disables p53 function. One such antagonist, called MDM2, is involved in sarcomas. Other antagonists are the “early proteins” produced by cancer-causing strains of the human papillomavirus (see the section Cancer-causing agents: Human papillomaviruses).
Other tumour suppressor genes
Other tumour suppressor genes that have been discovered through the study of familial cancers include the BRCA1 and BRCA2 genes, which are associated with about 5 percent of hereditary breast cancers; the APC gene, linked to familial adenomatous polyposis coli (a hereditary form of colon cancer that causes thousands of polyps to form in the colon, some of which can become cancerous); the WT1 gene, involved in Wilms tumour of the kidney; the VHL gene, associated with kidney cancer and von Hippel-Lindau disease; and the NF1 and NF2 genes, responsible for certain forms of neurofibromatosis.
Tumour suppressor genes discovered through the study of hereditary cancers also play a role in sporadic cancers. For example, hereditary melanoma is associated with a loss of function of the tumour suppressor gene called MTS1 (from multiple tumour suppressor), which also goes awry in a variety of sporadic tumours. MTS1 codes for a protein called p16. When functioning properly, the p16 protein prevents the cell cycle from progressing from the G1 stage to the S stage through an interaction with the RB protein. In cells in which p16 function is lost, the transition from G1 to S is not slowed. This transition point in the cell cycle seems to be extremely important to cellular health, since about 80 percent of human tumours exhibit a problem there.
DNA repair defects
DNA repair mechanisms are involved in maintaining the integrity of DNA, which often acquires errors during replication. When the cellular mechanisms that repair errors in the DNA are damaged—through acquired or inherited alterations—the rate of genetic mutation increases by several orders of magnitude.
Defects in two mismatch repair genes, called MSH2 and MLH1, underlie one of the most common syndromes of inherited cancer susceptibility, hereditary nonpolyposis colon cancer. This form of colon cancer accounts for 15 to 20 percent of all colon cancer cases. Inherited or acquired alterations in the mismatch repair genes allow mutations—specifically point mutations and changes in the lengths of simple sequence repetitions—to accumulate rapidly (behaviour referred to as a mutator phenotype). Since this defect is inherited by all the cells in the body, it is not known why some organs are more susceptible to cancer development than others.
Another type of repair system that can malfunction is one that corrects defects inflicted on DNA by ultraviolet radiation, a major constituent of sunlight (see the section Cancer-causing agents: Radiation). This kind of radiation damage involves the fusion of two nucleotide bases called pyrimidines to form a “pyrimidine dimer.” Normally, the repair system removes the dimer from the DNA and replaces it with two undamaged nucleotides. Malfunction of the repair pathway, on the other hand, is responsible for two inherited disorders, xeroderma pigmentosum and Cockayne syndrome.
Apoptosis and cancer development
Many cells undergo programmed cell death, or apoptosis, during fetal development. Apoptosis also may occur when a cell becomes damaged or deregulated, as is the case during tumour development and other pathological processes. Thus, when functioning properly, the body can induce apoptosis to rid itself of cancer cells.
Not all cancer cells succumb in this manner, however. Some find ways to escape apoptosis. Two mutations identified in human tumours lead to a loss of programmed cell death. One mutation inactivates the p53 gene, which normally can trigger apoptosis. The second mutation affects a proto-oncogene called bcl-2, which codes for a protein that blocks cell suicide. When mutated, the bcl-2 gene produces excessive amounts of the bcl-2 protein, which prevents the apoptosis program from being activated. Malignant lymphomas that stem from B lymphocytes exhibit this bcl-2 behaviour. The alteration of the bcl-2 gene is caused by a chromosomal translocation that keeps the gene in a permanent “on” position. Loss of p53 function protects cells from only certain kinds of suicide, whereas the bcl-2 alteration completely blocks access to apoptosis.
The blocking of apoptosis is thought to be an important mechanism in tumour generation. This mutation also may contribute to the development of tumours that are resistant to radiation and drug therapies, most of which destroy cancer cells by inducing apoptosis in them. If some cells within a tumour are unable to commit suicide, they will survive treatment and proliferate, creating a tumour refractory to therapy of this type. In this way apoptosis-inducing therapies may actually select for cancer cells resistant to apoptosis.
Telomeres and the immortal cell
Immortalization is another way that cells escape death. Normal cells have a limited capacity to replicate, and so they age and die. The processes of aging and dying are regulated in part by DNA segments called telomeres, which are found at the ends of chromosomes. Telomeres shorten every time chromosomes are replicated and the cell divides. Once they have been reduced to a certain size, the cell reaches a crisis point, is prevented from dividing further, and dies.
This form of growth control appears to be inactivated by oncogenic expression or tumour suppression activity. In cells undergoing malignant transformation, telomeres do shorten, but, as the crisis point nears, a formerly quiescent enzyme called telomerase becomes activated. This enzyme prevents the telomeres from shortening further and thereby prolongs the life of the cell.
Most malignant tumours—including breast, colon, prostate, and ovarian cancers—exhibit telomerase activity, and the more advanced the cancer, the greater the frequency of detectable telomerase in independent samples. If cell immortality contributes to the growth of most cancers, telomerase would appear to be an attractive target for therapy.
Cancer-causing agents
Cancer-causing agents can be categorized into three groups: oncogenic viruses, chemicals, and radiation. All three lead to the molecular mechanisms of cancer described in the section The molecular basis of cancer.
Oncogenic viruses
A large number of DNA and RNA viruses cause tumours in animals, but in humans it is the DNA viruses that are implicated in most forms of cancer. Only one RNA virus is known to cause cancer in humans. The precise role that viruses play in tumour genesis is not clear, but it seems that they are responsible for causing only one in the series of steps necessary for cancer to develop.
DNA viruses
Three DNA viruses—human papillomaviruses, the Epstein-Barr virus, and the hepatitis B virus—are linked to tumours in humans.
Human papillomaviruses
More than 70 types of human papillomavirus (HPV) have been described. Some cause benign papillomas of the skin (warts). Other strains, particularly HPV-16 and HPV-18, are linked to genital and anal cancers. These viruses are sexually transmitted. HPV-16 and HPV-18 are found in the majority of squamous-cell carcinomas of the uterine cervix. Genital warts with low malignant potential are associated with HPV-6 and HPV-11.
When transforming DNA viruses infect a cell, they integrate their DNA into the genome of the host. At this point the virus does not reproduce but only produces the proteins necessary to commandeer the DNA synthesis machinery of the host cell. Two of these viral genes, E6 and E7, can act as oncogenes. The proteins they encode bind to the protein products of two important tumour suppressor genes, p53 and RB, respectively, knocking these proteins out of action and allowing the cell to grow and divide.
The E6 and E7 proteins of HPV-16 and HPV-18 bind to the RB and p53 proteins very tightly; in contrast, the E6 and E7 proteins of HPV-6 and HPV-11 (the low-risk types) bind RB and p53 with low affinity. The differences in binding ability of these proteins correlate with their ability to activate cell growth, and they are consistent with the differences in malignant potential of these virus strains.
Epstein-Barr virus
Epstein-Barr virus (EBV) is a type of herpesvirus that is well known for causing mononucleosis. It also contributes to the pathogenesis of four human tumours: the African form of Burkitt lymphoma, B-cell lymphomas in individuals whose immune systems are impaired from human immunodeficiency virus (HIV, the causative virus of AIDS) infection or the use of immunosuppressant drugs in organ transplantation, nasopharyngeal carcinoma, and some kinds of Hodgkin disease. EBV infects B lymphocytes, one of the principal infection-fighting white blood cells of the immune system. It does not replicate within the B cells; instead, it transforms them into lymphoblasts, which have an indefinite life span. In other words, the virus renders these cells immortal.
Burkitt lymphoma is endemic in certain areas of equatorial Africa and occurs sporadically in other parts of the world. As is the case with other cancer-inducing viruses, it is likely that EBV serves as only the first step toward malignant transformation and that additional mutations are required for bringing about this process.
Hepatitis B virus
Hepatitis B virus (HBV) is endemic in Southeast Asia and sub-Saharan Africa, areas that have the world's highest incidence of hepatocellular carcinoma (liver cancer). This and other epidemiological observations, as well as experimental evidence in animal models, have established a clear association between HBV and liver cancer. The precise role of hepatitis B virus in causing liver cancer is not yet understood, but evidence suggests that viral proteins disrupt signal transduction and thereby deregulate cell growth.
RNA viruses
Retroviruses have provided some of the most important insights into the molecular cell biology of cancer (see the section Retroviruses and the discovery of oncogenes), and yet only one human retrovirus, the human T-cell leukemia virus type I (HTLV-I), is linked to a human tumour. This virus is associated with a T-cell leukemia/lymphoma that is endemic in the southern islands of Japan and the Caribbean basin but that also is occasionally found elsewhere. HTLV-I infects helper T lymphocytes (the same type of cell that is infected by HIV). Infection occurs when infected T cells are transmitted via sexual intercourse, blood transfusion, or breast feeding. Only about 1 percent of infected individuals will develop leukemia, and then only after a period of 20 to 30 years.
HTLV-I differs from other oncogenic retroviruses in that it does not contain a viral oncogene and does not integrate into specific sites of the human genome to disrupt proto-oncogenes. Although the mechanism of transformation is not clear, a viral protein named tax, which promotes DNA transcription, may be involved in setting up an autocrine (self-stimulating) loop that causes continuous proliferation of infected T cells. When cells are constantly dividing, they are at greater risk from secondary transforming events (mutations) that will ultimately lead to the development of cancer.
Chemicals
Numerous chemicals are known to cause cancer in laboratory animals, and some of these substances have been shown to be carcinogenic for humans as well. Many of these chemicals carry out their effects only on specific organs. (See the table of chemical carcinogens.)
Experiments with chemical compounds demonstrate that the induction of tumours involves two clear steps: initiation and promotion. Initiation is characterized by permanent, heritable damage to a cell's DNA. A chemical capable of initiating cancer—a tumour initiator—sows the seeds of cancer but cannot elicit a tumour on its own. For tumour progression to occur, initiation must be followed by exposure to chemicals capable of promoting tumour development. Promoters do not cause heritable damage to the DNA and thus on their own cannot generate tumours. Tumours ensue only when exposure to a promoter follows exposure to an initiator.
The effect of initiators is irreversible, whereas the changes brought about by promoters are reversible. Many chemicals, known as complete carcinogens, can both initiate and promote a tumour; others, called incomplete carcinogens, are capable only of initiation.
Initiators
Compounds capable of initiating tumour development may act directly to cause genetic damage, or they may require metabolic conversion by an organism to become reactive. Direct-acting carcinogens include organic chemicals such as nitrogen mustard, benzoyl chloride, and many metals. Most initiators are not damaging until they have been metabolically converted by the body. Of course, one's metabolism can also inactivate the chemical and disarm it. Thus, the carcinogenic potency of many compounds will depend on the balance between metabolic activation and inactivation. Numerous factors—such as age, sex, and hormonal and nutritional status—that vary between individuals can affect the way the body metabolizes a chemical, and this helps to explain why a carcinogen may have different effects in different persons.
Proto-oncogenes and tumour suppressor genes are two critical targets of chemical carcinogens. When an interaction between a chemical carcinogen and DNA results in a mutation, the chemical is said to be a mutagen. Because most known tumour initiators are mutagens, potential initiators can be tested by assessing their ability to induce mutations in a bacterium (Salmonella typhimurium). This test, called the Ames test, has been used to detect the majority of known carcinogens.
Some of the most potent carcinogens for humans are the polycyclic aromatic hydrocarbons, which require metabolic activation for becoming reactive. Polycyclic hydrocarbons affect many target organs and usually produce cancers at the site of exposure. These substances are produced through the combustion of tobacco, especially in cigarette smoking, and also can be derived from animal fats during the broiling of meats. They also are found in smoked fish and meat. The carcinogenic effects of several of these compounds have been detected through cancers that develop in industrial workers. For example, individuals working in the aniline dye and rubber industries have had up to a 50-fold increase in incidence of urinary bladder cancer that was traced to exposure to heavy doses of aromatic amine compounds. Workers exposed to high levels of vinyl chloride, a hydrocarbon compound from which the widely used plastic polyvinyl chloride is synthesized, have relatively high rates of a rare form of liver cancer called angiosarcoma.
There also are chemical carcinogens that occur naturally in the environment. One of the most important of these substances is aflatoxin B1; this toxin is produced by the fungi Aspergillus flavus and A. parasiticus, which grow on improperly stored grains and peanuts. Aflatoxin B is one of the most potent liver carcinogens known. Many cases of liver cancer in Africa and East Asia have been linked to dietary exposure to this chemical.
Promoters
The initial chemical reaction that produces a mutation does not in itself suffice to initiate the carcinogenic process in a cell. For the change to be effective, it must become permanent. Fixation of the mutation occurs through cell proliferation before the cell has time to repair its damaged DNA. In this way the genetic damage is passed on to future generations of cells and becomes permanent. Because many carcinogens are also toxic and kill cells, they provide a stimulus for the remaining cells to grow in an attempt to repair the damage. This cell growth contributes to the fixation of the genotoxic damage.
The major effect of tumour promoters is the stimulation of cell proliferation. Sustained cell proliferation is often observed to be a factor in the pathogenesis of human tumours. This is because continuous growth and division increases the risk that the DNA will accumulate and pass on new mutations.
Evidence for the role of promoters in the cause of human cancer is limited to a handful of compounds. The promoter best studied in the laboratory is tetradecanoyl phorbol acetate (TPA), a phorbol ester that activates enzymes involved in transmitting signals that trigger cell division. Some of the most powerful promoting agents are hormones, which stimulate the replication of cells in target organs. Prolonged use of the hormone diethylstilbestrol (DES) has been implicated in the production of postmenopausal endometrial carcinoma, and it is known to cause vaginal cancer in young women who were exposed to the hormone while in the womb. Fats, too, may act as promoters of carcinogenesis, which possibly explains why high levels of saturated fat in the diet are associated with an increased risk of colon cancer.
Radiation
Among the physical agents that give rise to cancer, radiant energy is the main tumour-inducing agent in animals, including humans.
Ultraviolet radiation
Ultraviolet (UV) rays in sunlight give rise to basal-cell carcinoma, squamous-cell carcinoma, and malignant melanoma of the skin. The carcinogenic activity of UV radiation is attributable to the formation of pyrimidine dimers in DNA. Pyrimidine dimers are structures that form between two of the four nucleotide bases that make up DNA—the nucleotides cytosine and thymine, which are members of the chemical family called pyrimidines. If a pyrimidine dimer in a growth regulatory gene is not immediately repaired, it can contribute to tumour development (see the section The molecular basis of cancer: DNA repair defects).
The risk of developing UV-induced cancer depends on the type of UV rays to which one is exposed (UV-B rays are thought to be the most dangerous), the intensity of the exposure, and the quantity of protection that the skin cells are afforded by the natural pigment melanin. Fair-skinned persons exposed to the sun have the highest incidence of melanoma because they have the least amount of protective melanin.
It is likely that UV radiation is a complete carcinogen—that is, it can initiate and promote tumour growth—just as some chemicals are.
Ionizing radiation
Ionizing radiation, both electromagnetic and particulate, is a powerful carcinogen, although several years can elapse between exposure and the appearance of a tumour. The contribution of radiation to the total number of human cancers is probably small compared with the impact of chemicals, but the long latency of radiation-induced tumours and the cumulative effect of repeated small doses make precise calculation of its significance difficult.
The carcinogenic effects of ionizing radiation first became apparent at the turn of the 20th century with reports of skin cancer in scientists and physicians who pioneered the use of X rays and radium. Some medical practices that used X rays as therapeutic agents were abandoned because of the high increase in the risk of leukemia. The atomic explosions in Japan at Hiroshima and Nagasaki in 1945 provided dramatic examples of radiation carcinogenesis: after an average latency period of seven years, there was a marked increase in leukemia, followed by an increase in solid tumours of the breast, lung, and thyroid. A similar increase in the same types of tumours was observed in areas exposed to high levels of radiation after the Chernobyl disaster in Ukraine in 1986. Electromagnetic radiation is also responsible for cases of lung cancer in uranium miners in central Europe and the Rocky Mountains of North America.
Inherited susceptibility to cancer
Not everyone who is exposed to an environmental carcinogen develops cancer. This is so because, for a large number of cancers, environmental carcinogens work on a background of inherited susceptibilities. It is likely in most cases that cancers arise from a combination of hereditary and environmental factors.
Familial cancer syndromes
Although it is difficult to define precisely which genetic traits determine susceptibility, a number of types of cancer are linked to a single mutant gene inherited from either parent. In each case a specific tissue organ is characteristically affected. These types of cancer frequently strike individuals decades before the typical age of onset of cancer. Hereditary cancer syndromes include hereditary retinoblastoma, familial adenomatous polyposis of the colon, multiple endocrine neoplasia syndromes, neurofibromatosis types 1 and 2, and von Hippel-Lindau disease. The genes responsible for these syndromes have been cloned and characterized, which makes it possible to detect those who carry the defect before tumour formation has begun. Cloning and characterization also open new therapeutic vistas that involve correcting the defective function at the molecular level. Many of these syndromes are associated with other lesions besides cancer, and in such cases detection of the associated lesions may aid in diagnosing the syndrome.
Certain common types of cancer show a tendency to affect some families in a disproportionately high degree. If two or more close relatives of a patient with cancer have the same type of tumour, an inherited susceptibility should be suspected. Other features of these syndromes are early age of onset of the tumours and multiple tumours in the same organ or tissue. Genes involved in familial breast cancer, ovarian cancer, and colon cancer have been identified and cloned.
Although tests are being developed—and in some cases are available—to detect mutations that lead to these cancers, much controversy surrounds their use. One dilemma is that the meaning of test results is not always clear. For example, a positive test result entails a risk—not a certainty—that the individual will develop cancer. A negative test result may provide a false sense of security, since not all inherited mutations that lead to cancer are known.
Syndromes resulting from inherited defects in DNA repair mechanisms
Another group of hereditary cancers comprises those that stem from inherited defects in DNA repair mechanisms. Examples include Bloom syndrome, ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum. These syndromes are characterized by hypersensitivity to agents that damage DNA (e.g., chemicals and radiation). The failure of a cell to repair the defects in its DNA allows mutations to accumulate, some of which lead to tumour formation. Aside from a predisposition to cancer, individuals with these syndromes suffer from other abnormalities. For example, Fanconi anemia is associated with congenital malformations, a deficit of blood cell generation in the bone marrow (aplastic anemia), and susceptibility to leukemia. Children with Bloom syndrome have poorly functioning immune systems and show stunted growth.
Milestones in cancer science
The types of cancer that cause easily visible tumours have been known and treated since ancient times. Mummies of ancient Egypt and Peru, dating from as long ago as 3000 BC, exhibit signs of the disease in their skeletons. About 400 BC the Greek physician Hippocrates used the term carcinoma—from the Greek karcinos, meaning “crab”—to refer to the shell-like surface, leglike filaments, and sharp pain often associated with tumours.
Speculations about the factors involved in cancer development have been made for centuries. About AD 200 the Greco-Roman physician Galen of Pergamum attributed the development of cancer to inflammation. A report in 1745 of familial cancer suggested that hereditary factors are involved in the causation of cancer. The English physician John Hill, in a 1761 paper noting a relationship between tobacco snuff and nasal cancer, was the first to point out that substances found in the environment are related to cancer development. Another English physician, Sir Percivall Pott, offered the first description of occupational risk in 1775 when he attributed high incidences of scrotal cancer among chimney sweeps to their contact with coal soot. Pott hypothesized that tumours in the skin of the scrotum were caused by prolonged contact with ropes that were saturated with chemicals found in soot. He noted that some men with scrotal cancer had not worked as chimney sweeps since boyhood—an observation suggesting that cancer develops slowly and may not give rise to clinical manifestations until long after exposure to a causal agent.
In the 1850s the German pathologist Rudolf Virchow formulated the cell theory of tumours, which stated that all cells in a tumour issue from a precursor cancerous cell. This theory laid the foundation for the modern approach to cancer research, which regards cancer as a disease of the cell.
By the end of the 19th century, it was clear that progress in understanding cancer would require intensive research efforts. To address this need a number of institutions were set up, including the Cancer Research Fund in Britain in 1902 (renamed the Imperial Cancer Research Fund two years later). To promote cancer education in the United States, the American Society for the Control of Cancer was founded in 1913; in 1945 it was renamed the American Cancer Society.
In the early years of the 20th century, researchers focused their attention on the transmission of tumours by cell-free extracts. This research suggested that an infectious agent found in the extracts was the cause of cancer. In 1908 two Danish pathologists, Vilhelm Ellermann and Oluf Bang, reported that leukemia could be transmitted in chickens by means of a cell-free filtrate obtained from a chicken with the disease. In 1911 the American pathologist Peyton Rous demonstrated that a sarcoma (another type of cancer) could be transmitted in chickens through a cell-free extract. Rous discovered that the sarcoma was caused by a virus—now called the Rous sarcoma virus—and for this work he was awarded the 1966 Nobel Prize for Physiology or Medicine.
In 1915 Japanese researchers Yamagiwa Katsusaburo and Ichikawa Koichi induced the development of malignant tumours in rabbits by painting the rabbits' ears with coal tar and thus showed that certain chemicals could cause cancer. Subsequent studies showed that exposure to certain forms of energy, such as X rays, could induce mutations in target cells that led to their malignant transformation.
Viral research in the 1960s and '70s contributed to current understanding of the molecular mechanisms involved in cancer development. Much progress was made as a result of the development of laboratory techniques such as tissue culture, which facilitated the study of cancer cells and viruses. In 1968 researchers demonstrated that when a transforming virus (a virus capable of causing cancer) infects a normal cell, it inserts one of its genes into the host cell's genome. In 1970 one such gene from the Rous sarcoma virus, called src, was identified as the agent responsible for transforming a healthy cell into a cancer cell. Later dubbed an oncogene, src was the first “cancer gene” to be identified. (See the section Causes of cancer: Retroviruses and the discovery of oncogenes.) Not long after this discovery, American cell biologists Harold Varmus and J. Michael Bishop found that viral oncogenes come from normal genes (proto-oncogenes) that are present in all mammalian cells and that normally play a critical role in cellular growth and development.
The concept that cancer is a specific disturbance of the genes—an idea first proposed by Theodor Boveri in 1914—was strengthened as cancer research burgeoned in the 1970s and '80s. Researchers found that certain chromosomal abnormalities were consistently associated with specific types of cancer, and they also discovered a new class of genes—tumour suppressor genes—that contributed to cancer development when damaged.
Since that time scientists have discovered many more defective growth-regulating genes that are involved in the malignant transformation of the cell. From this work it has become clear that cancer develops through the progressive accumulation of damage in different classes of genes—oncogenes, tumour suppressor genes, and mismatch repair genes—and it is through the study of these genes that the current understanding of cancer has emerged.
José Costa
Additional Reading
Search for the cure
A special issue of Scientific American, “What You Need to Know About Cancer” (September 1996), also available in book form with the same title (1997), offers a comprehensive overview of cancer written for the scientifically inclined person.
Robert A. Weinberg, Racing to the Beginning of the Road: The Search for the Origin of Cancer (1996, reissued 1998), a highly personal and lucid story that makes the difficult field of cancer biology understandable to most readers.
Michael Waldholz, Curing Cancer: The Story of the Men and Women Unlocking the Secrets of Our Deadliest Illness (1997, reissued 1999), a popular account of what goes on behind the scenes, with candid portrayals of the major actors.
Helene G. Brown, John R. Seffrin, and Clement Bezold (eds.), Horizons 2013 (1996), a forward-looking volume exploring future possible scenarios for the prevention and treatment of cancer.
Facts on Cancer
Cancer Facts & Figures (annual), published by the American Cancer Society, a compilation of rates and trends of cancer in the U.S. population, useful as a comprehensive source of statistics.
Marion Morra and Eve Potts, Choices, 2nd rev. ed. (1994), a direct and useful discussion of the many questions confronted by cancer patients and their families.
Roberta Altman and Michael J. Sarg, The Cancer Dictionary, rev. ed. (1999), a concise guide to cancer-related terminology.
Coping with cancer
Gerald P. Murphy, Lois B. Morris, and Dianne Lange, Informed Decisions (1997), a complete discussion of the many issues facing the cancer patient.
Action Guide for Healthy Eating (1995), published by the National Cancer Institute, a pamphlet offering dietary recommendations based on the best available scientific evidence.
Eating Hints for Cancer Patients: Before, During, & After Treatment (1998), published by the National Cancer Institute, a patient-oriented booklet containing pertinent and useful nutritional information.
Elise NeeDell Babcock, When Life Becomes Precious: A Guide for Loved Ones and Friends of Cancer Patients (1997), a guide for transforming a devastating situation into an empowering and positive experience.
Bill Soiffer, Life in the Shadow: Living with Cancer (1991), a vivid account of surviving Hodgkin disease.