Carcinogenesis Susan C. McMillan

T

HE CAUSES OF cancer are many and varied. In the minds of the lay public, cancer is caused by environmental pollutants in our food, water, and air. This simplistic view of cancer causation may contribute to the misconception that we have no control over our own cancer risk. Although there certainly are carcinogens in the air we breathe, the water we drink, and the food we eat, these are insignificant compared with those things that we can control in our environment. ’ Carcinogens are substances that, when introduced into a cell, cause changes in the structure and function of the cell that lead to cancer. Carcinogens are classified as chemical, radiation, or viral, and their effects may be enhanced or reduced by host factors such as genetic susceptibility.‘-3 There are two ways that substances are identified as carcinogens. First, epidemiological studies may show patterns of tumor development in certain populations that suggest causality. Second, animal studies may show a cause and effect relationship between a suspected substance and a tumor. Unfortunately, it is almost impossible to estimate the degree of human risk using evidence from animals because of species-specific responses. However, a combination of the several sources of data may provide important information about which substances are carcinogenic. ’ Not only are carcinogens often species-specific, they are also often disease-specific. Substances that greatly enhance the risk of one type of cancer may have little or no effect on other types. Thus, cancers of different organs should generally be considered as independent diseases with different causes. ’ It is now believed that carcinogens work by interaction with existing proto-oncogenes and cancer From the College of Nursing, University of South Florida, Tampa, FL. Susan C. McMillan, PhD, RN: American Cancer Society Professor of Oncology Nursing, University of South Florida College of Nursing. Address reprint requests to Susan C. McMillan, PhD, RN, American Cancer Society Professor of Oncology Nursing, University of South Florida, College of Nursing, MDC Box 22, 12901 N Bruce B. Downs Blvd, Tampa, FL 33612. Copyright 0 1992 by W.B. Saunders Company 0749-2081/92/0801-0003$5.00/0

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suppressor genes in normal cells. All animals contain in their cells the genes to produce tumors when these genes are mutated. Proto-oncogenes are mutated and “switched on” by carcinogens such as chemicals, radiation, and viruses.4-7 STAGES OF CARCINOGENESIS

It is useful to describe carcinogenesis as taking place in three stages: initiation, promotion, and progression. Initiation occurs when a chemical, physical, or biological agent damages DNA. This damage may be reversible or may lead to a genetic mutation if not repaired. Such a mutation alone may not lead immediately to malignant growth; however, the cell may become susceptible to promotion at a later time.3 Cells that are initiated may or may not become malignancies. Promotion is usually the result of a second factor acting on the initiated cell and was described by Rous and Kidd* in 1941 in rabbits. Tar applied to the ears of the rabbits was the initiator and wounding of the tar-treated areas was the promotor. The combination led to the development of neoplasms along the edges of the wounds. Later, Mottram9 reported initiating tumors in mice with benzopyrene and then promoting the cellular changes with croton oil, a known irritant. Mottram reported a much higher rate of skin tumors when both initiator and promoter were used than when the initiator was used alone. Thus, agents that are carcinogens are known as initiators, and other agents capable of inducing neoplastic transformation only when applied after an initiator are known as promotors. Some carcinogenic agents are known as complete carcinogens because they can both initiate and promote neoplastic transformation. Initiation is dose-dependent; some complete carcinogens will only initiate in low doses but not promote.* Irreversibly initiated cells usually do not display their changes and so are not detectable until they are exposed to a promoting agent. The changes in cells that have undergone promotion are usually grossly visible.3 Cells that are irreversibly initiated may be promoted even after long latency periods. The latency period or tumor induction time may be an extended period in humans. The latency period varies with the type of agent, the dosage, and the Seminars in Oncology Nursing,

Vol 8, No 1 (February),

1992:

pp lo-19

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CARCINOGENESIS

characteristicsof the target cells.* There is a clear relationship betweentime sequenceand the effects of tumor initiation and promotion.” It is believed that promoting agents work by changing the expression of genetic information within the cell,” increasing DNA synthesis, increasinggeneamplification (increasing the number of copies of a particular gene), and altering intercellular communication.* Some hormones have been shown to be very effective promoting agents in humans.i For example, estrogenhasbeenlinked to liver adenomas,‘*breast cancer,13and endometrial cancer.l4 Evidence of the effects of estrogen has been gained not only in animal trials but also from experience with women who have had reduced incidence of breast cancerfollowing oophorectomy and anti-estrogen therapy.“15 Asbestosis believed to be a promoting agent in tracheal and bronchogenic carcinomas among smokers. However, asbestosis believed to be an initiator of mesotheliomaseven with brief exposure. Exposure to other promoting agents is, for the most part, under the control of the individual. For example, dietary fat, cigarette smoke, and alcohol are believed to act as promoting agents.* The third stageof carcinogenesisis progression. Progression involves morphological and phenotypic changes in the cell and is associatedwith increased malignant behavior leading to invasion of surrounding tissue and metastasis to distant body part~.~ CHEMICAL CARCINOGENESIS

Historical Perspective

In 1775, Sir Percival Pott, an English physician, noted that men who had been chimney sweepsas young boys were much more likely to develop scrotal cancer. Pott did not recommend any preventive action, but in 1778 the Danish Chimney Sweepers’ Guild recommendeddaily bathing. A century later there was a measurablyhigher rate of scrotal cancer in England where no change had been recommendedcompared with other parts of Europe.l6 In 1915, the first evidence of carcinogenesis gained through laboratory experimentation was reported. Yamagiwa and Ichikawa,17 Japanesepathologists, applied coal tar to the earsof laboratory animals, inducing skin tumors. Thus began the modem approachof combining laboratory research

with epidemiological evidence to understand chemical carcinogenesis. Mechanisms of Action

Results of the work of Miller16 and Miller18*19 led to the theory that many carcinogens are actually precarcinogensthat must be somehow metabolized by the cell in order to exert their effect. It has been proposedthat chemical carcinogensmay be convertedinto chemicalswith electron-deficient sites (electrophilic reactants) that exert their biological effect by interaction with DNA. In addition, during the metabolismof the carcinogen, free radicals may be formed that carry no charge but that do possessa single uppaired electron, making the free radical extremely reactive.16.18,19 Antioxidants such as vitamins A, C, and E inhibit the formation of free radicals and thus also may inhibit the damagingeffect of many chemical carcinogens on DNA. Becausethe majority of chemical carcinogens must be metabolized in the cell before exerting their carcinogenic activity, substancesthat are carcinogenic for one speciesmay not be carcinogenic for another becauseof the differences in metabolismamong species.Although both saccharin and dioxin in insecticides are promotersof cancer in experimental studies in animals, they have not beenshown to have the sameeffect in humans. Although it is not known to be a carcinogen in lower animals, benzeneis known to induce leukemia in humans.’ ** Categories of Chemical Carcinogens

Many agentshave been called chemical carcinogens. Some have been confirmed to be carcinogenic through research,but many have not. Table 1 presents some confirmed carcinogens and the human cancerswith which they are associated. Dietary carcinogens. Although many Americans believe that they are helpless to prevent cancer, experts now believe that many cancerscould be avoided by changes in diet. Strong evidence may be found in the link betweencertain elements in the diet and cancer incidence. One areaof concernamongthe lay public is fear of ingesting powerful direct-acting carcinogens. Although there are carcinogens in natural foods and plant products, theseare not a major risk factor for cancersin the United States.Of someconcern are the precursorsof carcinogensthat may be ingested. For example, benzopyrene may be pro-

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SUSAN Table 1. Chemical Carcinogens and Associated Human Cancers Chemical

Carcinogens

Tobacco smoke Smokeless tobacco Dietary fat Alcohol Polycyclic aromatic hydrocarbons Benzene Aflatoxin Bl Chromium compounds Nickel compounds Asbestos Asbestos plus smoking Vinyl chloride Data from

Associated

Cancers

Lung, esophageal, bladder Buccal mucosa Colon, breast Head and neck, liver Skin, lung Leukemia Liver Lung Lung, nasal sinuses Lung, pleura, peritoneum Lung Liver

Doll and Pete’ and Pitot.*

duced when meat or fish is charcoal broiled or smoked or when any food is fried in fat that has been used repeatedly. Therefore, benzopyrene predisposes to stomach cancer, a type of cancer that is in the decline in the United States.20-22 Some ingested products provide the substrates for the formation of carcinogens in the body. For example, the powerful carcinogens known as nitrosamines may be formed from nitrites derived from nitrates that are ingested in vegetables and in foods to which nitrates have been added as a preservative. Foods preserved in this way include bacon and ham. Formation of the nitrites is assisted by tobacco smoke and requires either bacterial assistance or a mildly acidic environment. Formation of these nitrosamines is inhibited by the presence of antioxidants such as vitamin C in the stomach.23’24 A significant area of concern at present is the production of carcinogens by microorganisms in stored foods. For example, aflatoxin, a product of the Aspergillisflavus fungus, is present in moldy peanuts, corn, and other foods that are stored in hot, humid climates. Aflatoxin is one of the most powerful liver carcinogens, and the presence of the hepatitis B virus appears to greatly enhance this risk. Seen primarily in tropical countries, cancer of the liver is relatively rare in the United States accounting for less than 1% of cancer deaths.25 The dietary element thought to have the greatest impact on cancer incidence in the United States is fat. It is believed that certain fats may contribute to the production of carcinogens by increasing the amount of bile acids and cholesterol metabolites in

C. McMILLAN

the feces. Substances like deoxycholic and lithochohc acid are found in the stools of Western populations who are known to have a higher risk of colon cancer. These substances are found in lesser amounts in the stools of Asians and Africans in whom colon cancer is known to be much less prevalent. Larger amounts are also found in the stools of patients who have polyps in the colon. These substances have been experimentally increased in humans by giving them high-fat, high-meat diets. Low levels of serum cholesterol have been associated with colon cancer.26-28 Fiber in the diet is believed by some to exert its effect by affecting the transport and concentration of colonic carcinogens. Bulk in the diet makes feces move more quickly through the alimentary canal, thus decreasing the amount of time carcinogens are in contact with the wall of the bowel. However, research has suggested a more precise role for fiber. Primary bile acids are converted into secondary bile acids in the presence of anaerobic bacteria in the colon. It is the secondary bile acids, lithocholic acid and deoxycholic acid, that are promoters. When dietary fiber ferments, it produces oxygen which has an inhibiting effect on anaerobic bacteria thus decreasing production of secondary bile acids. The presence of fiber has the effect of actually reducing the amounts of lithocholic and deoxycholic acid in the bowe1.28-30 Some elements in the diet are also believed to deactivate or prevent formation of certain carcinogens. For example, selenium and vitamins A, C, and E are believed to be protective in normal doses. In fact, experimental studies seem to suggest that vitamin A can actually reduce the probability that an initiated cell will become fully transformed into a cancerous ce11.31-33 Obesity has been positively associated in epidemiological studies with a variety of common cancers , including endometrial , cervical, colorectal, ovarian, breast, and prostate cancer. Of these, the strongest association is between endometrial cancer and obesity; the weakest association is with cancer of the prostate.34-36 Use of alcohol as a beverage has long been associated with cancers of the head and neck. Alcohol is believed to affect the transport of carcinogens. Specifically, alcohol facilitates the contact between an externally introduced carcinogenic chemical and the contents of the stem cells that line

13

CARCINOGENESIS

the upper digestive tract and the larynx. The carcinogenic effects of cigarette smoke may be enhanced by concomitant consumption of alcohol.’ Chemicals in the workplace. Since Sir Percival Pott first identified soot as a carcinogen, many other occupational chemicals have been identified and to a large extent eliminated or controlled. Working with asbestoshas long been associated with cancers of the lung and with mesothelioma of the pleura and peritoneum. However, the highest incidence of cancer has been in smokers. It appearsthat there is a synergistic effect between asbestosand smoking. Asbestosis currently being removed from many homesand offices, and smoking has been greatly curtailed in many work settings.2*37Cancer deaths attributable to occupational factors are believed to be decreasing,largely due to the attention paid to carcinogens in the workplace in recent years.i It is estimatedthat more than 30% of current US cancerdeathsare related to tobacco, making smoking a leading preventable cause of cancer today. Epidemiological evidence of the carcinogenic effect of tobacco is overwhelming. In countries where smoking is prevalent, lung cancerincidence is much higher. For example, bronchogenic carcinoma is 35 times more prevalent in England than in parts of West Africa. As cigarette smoking has increasedamong women, lung cancer deathshave also increased.’ In fact, lung cancer has now surpassedbreastcancer as the leading causeof cancer deaths among American women.38 Cigarette smoke, a complete carcinogen, is capable of both initiation and promotion. Not only is the smokerat risk, but others sharing the smoker’s environment are also at risk. Passive smoking involves inhaling both mainstreamsmoke (inhaled and exhaled by the smoker) and sidestream smoke (issues from the end of the cigarette). Many of the 50 carcinogenic substancesin cigarette smoke are believed to be presentin environmental tobacco smoke. Although results of studies linking passive smoking with lung cancer have been mixed, there is sufficient evidence to believe that passive smoking increaseslung cancer risk.39 Testing Chemical Carcinogens

Identification of carcinogenic substancesis essential to cancer prevention. Two major ap-

proacheshave been used to test chemical carcinogens. One involves exposure of test animals to suspectedcarcinogens.This type of procedure can be lengthy and is prohibitively expensive because of the large number of chemicals that need testing.2 Because of the time and expense involved in inducing tumors in live animals, great effort has been directed at developing screening tests using bioassay. These tests are designedto evaluate the effect of a given chemical (suspectedcarcinogen) on the DNA of cultured cells. To conduct the test, the suspectchemical is applied to bacteria or mammalian cells grown in culture. The goal is to see whether the test chemical or its metabolites can causea changein the cellular DNA that is permanent (seen in both daughter cells after cell division), or a changethat is not directly detectablebut can causeparticular cellular side effects. A number of tests have resulted, the most widely used one being the Ames test.“* This test has been criticized because it only identifies mutagens, leading to a simplistic approach to identification of carcinogens. Carcinogenesis is a multistep process and involves more than just mutations and often the final carcinogen has been metabolizedby the body.40*41However, the Ames test has been useful in identifying mutagens and when combined with other available information, it is of some use.i RADIATION CARCINOGENESIS

Historical Review

The carcinogenic effects of radiation were first suspectednear the turn of the century shortly after the discovery of roentgenrays. The first cancersto be observed were of the skin. Thirty years later, the relationship betweencancersand radionuclides was suspectedwhen it was observed that painters of radium dial watch faceshad a high incidence of osteosarcomasand carcinomasof the mastoid and nasal sinuses. The atomic bombs that were dropped on Nagasaki and Hiroshima near the end of World War II exposed thousandsof people to sublethal dosesof radiation. The survivors, 7 to 10 years later, were found to have a higher than normal incidence of various cancers,particularly leukemia and multiple myeloma. It is also wellknown that individuals treated with radiation for

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Hodgkin’s diseaseare at higher risk for leukemia than the averageperson.42 In addition to such epidemiological data, the carcinogenic effects of radiation have been confirmed using numerouscell-culture and animal experiments. For example, it was demonstratedin 1928 that skin cancersin laboratory animals could be induced with radiation.42 Virtually all types of neoplasmshave been induced in animals with the useof radiation. However, animals exhibit marked differences in sensitivity to radiation among various types of tissue as do humans.43 Mechanism of Radiation Carcinogenesis Ionizing radiation has the ability to remove electrons from or add electrons to the atoms in the material through which it passes,including human tissues. The results vary depending on the dose of radiation involved. Radiation producesits carcinogenic effect by causing breaks in DNA strands. When there are many breaks, the effect is lethal to the cells. But when the breaks are few, as in lowdose radiation, repair can occur. Failure of repair or abnormal repair may result in mutation and subsequentdevelopment of tumors.42-44 Sourcesof Radiation Ionizing radiation may be divided into two major types: electromagneticradiation and particulate radiation. Electromagnetic radiation includes X rays and gamma rays. Particulate radiation includes electrons, protons, neutrons, alpha particles, and heavy ions.42Humansmay be exposedto radiation from a variety of sources.These include medical procedures for diagnosis and treatment, and naturally occurring sourcessuch as radon, radioactive mines, and sunlight. The propensity of radiation used for diagnosis and treatment to cause cancer has been welldocumented. For example, in the 1940s and 195Os,it was common to treat enlargedtonsils and adenoids with radiation.45 A study of 1,056 subjects who were irradiated during that period found palpable nodular thyroid diseasein 27% and a third of those who underwent surgery had thyroid cancer.46 A 1975 study of 100 adults who had been irradiated in the neck area during childhood showeda 7% incidence of thyroid carcinoma.47An earlier study by MacMahon4* demonstratedthat cancermortality was about 40% higher in children

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C. McMlLLAN

who had been exposedto radiation in utero, with increasedmortality most apparentbetween 5 and 7 years of age. Becauseof such risks, modem diagnostic radiation equipment has been refined to greatly reduce the dosage of radiation delivered and the useof radiation as therapy hasbeenlimited to malignant disease. A recently recognized sourceof radiation exposure is radon. Radon is a colorless, odorless gas that occurs naturally as a result of the radioactive decay of radium and uranium in the earth’s crust. There are areasof high radon concentration scattered acrossthe United States.Although normally releasedinto the atmosphere,radon can becomea problem if a building is placed over its source, trapping the radon gas.49soBuildings built to maximize energy conservationare most likely to cause problems. By decreasingthe amount of outdoor air that is allowed to leak in or be drawn into the building, fuel is saved. However, radon is also conservedin the building.49 The concentratedlevels in some homes, schools, and offices have caused some concern, especially about an increasedrisk of lung cancer. It has been suggested that perhaps as much as 25% of lung cancers in nonsmokersmay be attributable to radon gas exposure. According to the Environmental Protection Agency, as many as 8 million homesin the United States have dangerously high radon levels. Test kits for homes are relatively inexpensive and prevention involves venting the home to allow dispersion of the radon gas into the atmosphere.49s50 Early in this century, uranium miners had a relatively high incidence of lung and other cancers, especially if they were smokers.Mine safety practices have been changedtoday such that the incidenceof cancer in miners has dropped back into a range consistent with the rest of the population.’ Certainly, for the average person, exposure to sun provides the single greatestrisk of radiationrelated cancer. Despite warnings offered by companies selling cosmeticsand suntan lotions as well as the American Cancer Society, Americans continue to sit on beachesby the hour trying to get a “healthy tan.” The term “healthy tan” is an oxymoron. A tan is the result of exposureto radiation from the sun and as such cannot be healthy. A recent study shows that even among Florida nurses, a group who should know the importance of sunscreen,only 35% use sunscreenall or most of the time when they are in the sun.51

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CARCINOGENESIS

Not only has sun exposure been linked to squamous cell and basal cell carcinomas, it has also been implicated in malignant melanoma.Although squamouscell and basal cell carcinomas may be unsightly and uncomfortable to treat, they do not tend to metastasize and cause death. However, melanoma is a virulent cancer that metastasizes throughout the body and frequently causesdeath.38 The National Aeronautical and SpaceAdministration (NASA) announced in April, 1991, that stratosphericozone depletion is progressing more rapidly than anticipated. This ozone depletion has been linked to a number of chemicals releasedinto the atmosphere including chlorofluorocarbons (CFCs), halons, and carbon tetrachloride5’ and to natural gasesreleasedby volcanic eruptions. There is increasing concern about the long-term effectsof such ozone depletion.53354 Some have speculatedthat the increasing incidenceof melanomamay be related to the depletion of the ozone shield.55 Melanoma incidence has been increasing at an average rate of 4% per year,56and the current rate of malignant melanoma is estimatedto be twice as high as it was a decade ago.57 The exact cause of this increase is not known, but it is hypothesizedthat increasedexposure to ultraviolet B (UVB) radiation in sunlight is partly responsible. Depletion of stratospheric ozone may result in increasing levels of UVB. Longstreth56predicted in 1988that a 1% depletion of ozone will result in increasesof 1% to 2% in melanoma incidence. However, not all experts agree that the cause and effect relationship between ozone depletion and melanoma rates is so clear. Skolnick5* states that our conclusions may be premature. He points out that although the ozonelayer doesappearto have thinned out by 4% to 5% in the past 12 years, we have limited research to provide evidence that UV radiation reaching earth is increasing. This issue remains controversial, but ozone depletion and skin cancer will continue to generateserious concern. Controversies Ionizing radiation is clearly carcinogenic. However, major questions still remain about the magnitude of the risk from low dosesand how to identify individuals who are at the highest risk.59 The answersto thesequestionswill have important implications for cancer prevention.

A current controversy is the extent to which electromagnetic fields may be carcinogenic. A number of studies have been conducted that focused on the incidence of cancer in individuals who are living or working near electrical transmission equipment such as distribution lines, power stations, transformerstations, and distribution substations. Although someof these studieshave suggested that exposure to electromagnetic fields is related to a moderate increase in some types of leukemia and brain tumors, the study results have been challenged.6o-65 VIRAL CARCINOGENESIS

Historical Review The relationship between viruses and cancer in animals was first recognized in 1911 when a farmer brought a chicken suffering from an unusual growth to Dr. Peyton ROUS,a researcher. The chicken had a sarcomacausedby what later came to be known as the Rous sarcoma virus. Since that first discovery, scientists have uncovered relationships between various viruses and feline and bovine leukemia, lymphoma in chickens, papilloma in rabbits, and others.234 Although the relationship between viruses and various cancersin animals hasbeenrecognized for many years, the relationship between viruses and human cancer is a fairly recent discovery. And to date, only a few cancer causing viruses have been identified in humans (Table 2). Viruses work by affecting DNA and causing mutations. In somecases,the virus becomesintegrated into the chromosomesof the normal cell; in others, it alters chromosomestructure. The net result is activation of oncogenesand inactivation of cancer suppressorgenes.2*4

Table 2. Viruses Virus

Cancers

Associated Cancer

HBV HTLV-1 EBV

Hepatocellular carcinoma T-cell leukemia Burkitt’s lymphoma Nasopharyngeal carcinoma Kaposi’s sarcoma Cervical carcinoma Cervical carcinoma

HIV HPV HSV Data from

and Aeeocieted

Henderson,ss

Bartlett,p7

and Iwasaka.”

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Tumor Viruses Hepatitis B virus. Epidemiological data support the relationship between the hepatitis B virus (HBV) and hepatocellular carcinoma.3 For example, cancer of the liver is 100 times more prevalent in southeast Africa, where HBV is endemic, than in England. The incidence of liver cancer among black Americans is relatively low, similar to white Americans.’ HBV is also endemic in Asia, where the incidence of hepatocellular carcinoma is also very high.3 Human T-cell leukemia-lymphoma virus. Human T-cell leukemia-lymphoma virus (HTLV- 1) is a retrovirus thought to be responsible for some T-cell leukemias in adults.66 HTLV-1 is endemic in some parts of Japan, in areas of the Caribbean and Africa, and in the southeastern United States. ’ @ The virus, which appears to be transmitted by either sexual contact or contaminated blood, is known to have a latency period from several years to 40 years.3 HTLV-2 has been isolated in the T-cell variety of hairy cell leukemia. However, hairy cell leukemia is a disease of the B lymphocyte with relatively few cases affecting T lymphocytes. * The Epstein-Burr virus. The Epstein-Barr virus (EBV), which is endemic in parts of the African continent, is a DNA-type virus of the herpes family. It stimulates B lymphocytes to proliferate. When the host immune system is intact, the T cells control the proliferating B cells. However, when the immune system is dysfunctional following a disease (ie, malaria, the acquired immunodeficiency syndrome [AIDS], or cyclosporin administration), the T cells may lose the battle and a neoplasm such as Burkitt’s lymphoma may result.3 In the United States, Burkitt’s lymphoma is relatively rare. EBV is associated with the benign disease infectious mononucleosis. Hodgkin’s disease has been linked with EBV in the United States but the data are conflicting. In China, EBV is believed to be a causative factor in the high incidence of nasopharyngeal carcinomas. ’ $’ The human immunodeficiency virus. The human immunodeficiency virus (HIV) is a retrovirus that causes the condition that has become known as AIDS. Although not an oncogenic virus per se, HIV, through its suppression of the immune response, results in the development of opportunistic tumors such as Kaposi’s sarcoma. There are five known routes of transmission of HIV: sexual con-

SUSAN

C. McMlLLAN

tact, needle sharing, exposure to blood or blood products, through breast milk, and through the placenta while in utero. It is estimated that millions of individuals worldwide are infected with HIV but are, as yet, asymptomatic. Thus, although many oncology nurses have never seen Karposi’s sarcoma, its incidence may be expected to increase as more cases of AIDS are confirmed.67 Human papilloma viruses. Human papilloma viruses (HPV) affect squamous epithelium. This is the family of viruses that is responsible for common warts seen on the skin and genital warts, known as condylomas. DNA from HPV-16 and HPV-18 may be found in 70% of all cervical carcinomas. Although the association between HPV and cervical cancer is strong, the associations between HPV and cancer of the penis and prostate are less definitive. 1,3,66 Herpes simplex virus type II. Herpes simplex virus type II (HSV) is also sexually transmitted and has also been implicated in cervical cancer. For decades, sexual promiscuity was linked in epidemiological studies with cancer of the cervix. Today, the association is believed to be due to the sexual transmission of two oncogenic viruses, HPV and HSV. Current research suggests that multiple factors may account for the occurrence of cervical carcinoma and that HSV-II and HPV may actually be synergistic in causing the development of this cancer.66,68 GENETICS AND HEREDITY IN CANCER

We may wonder why some individuals who live an apparently healthy lifestyle die with cancer whereas individuals who have poor dietary and personal habits do not. The answer to why some individuals get cancer and others do not appears to lie at least in part in genetic makeup.’ There are a number of autosomal dominant diseases that are known to contribute to cancer risk. For example, familial polyposis increases risk of colon cancer, and dysplastic nevi predisposes to melanoma. Both of these conditions run in families. There are also autosomal recessive diseases that increase risk of certain cancers. For example, albinism increases the incidence of squamous cell carcinoma of the skinM Persons with inherited xeroderma pigmentosum have a marked inability to repair damage to DNA caused by the sun and therefore have an increased susceptibility to skin cancer.69

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CARCINOGENESIS

Malignant cells of many tumors have chromosomal defects. In some casesthe defect is a translocation (movement of genetic material from one chromosome to another), which could serve to place an oncogenenext to an activating DNA sequence. In somecasesthere is a deletion of a specific chromosome band, which could serve to eliminate a cancer suppressor gene. And in trisomy, there may be an extra gene that leads to expression of some abnormality.70 Severalcancershave been associatedwith chromosomalabnormalities. The Philadelphia chromosome, a translocation of the long arm of chromosome 22, is present in chronic myelogenous leukemia. Evidence from twins suggeststhat this is an acquired rather than an inherited abnormality.71 Down’s syndrome (trisomy 21) has beenidentified as a risk factor in leukemia, and familial renal cancer has been associatedwith deletion of chromosome 13.44 Thus, genetic makeup can be an important factor in cancer risk. Also important in individual cancer risk is age. Although cancercan be seenat all ages,the risk of cancerincreaseswith age. This escalatingrisk may be attributed to several factors including increased length of exposure to carcinogenswith longevity, increasedstatistical probability (the longer we live the more opportunities we have to get cancer), and a declining immune system.

SUMMARY

The rationale for identifying carcinogens and their mechanismsof action is twofold. First, carcinogens must be identified so they can be eliminated from our environment. And second, mechanisms must be identified that are involved in the conversion of a normal cell to a cancer cell. This knowledge will offer more approachesto cancer prevention.7 The ability to prevent many common fatal cancers caused by environmental agents was recognized by an expert committee of the World Health Organization in 1964.72Their report representeda consensusof expert opinion at that time. Since that report, some writers have suggestedthat as many as 80% to 90% of cancersare preventable.’ More conservativeestimatesrange from 40% to 50%.2 Preventing only 40% of cancers(the most conservative estimate) would result in saving thousandsof lives every year. Therefore, all members of the health care team must take an active role in cancer prevention. The nurse’s role in cancer prevention is one of education of the public. As more information about carcinogensbecomesavailable, nursesneed to sharethat information so that individuals are better able to make healthy choices for themselvesthat will lead to a lower incidence of cancer, our ultimate goal.

REFERENCES 1. Doll R, Peto R: The causes of cancer: Quantitative estimate of avoidable risks of cancer in the United States today. J Nat1 Cancer Inst 66:1191-1308, 1981 2. Pitot HC: Principles of cancer biology: Chemical carcinogenesis, in DeVita VT, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, Vol 1. Philadelphia, PA, Lippincott, 1985, pp 79-99 3. Yarbro JW: Carcinogenesis, in Groenwald SL, Frogge MH, Goodman M, Yarbro CH (eds): Cancer Nursing: Principles and Practice. Boston, MA, Jones & Bartlett, 1990, pp 31-42 4. Varmus HE: Viruses, genes, and cancer: I. The discovery of cellular oncogenes and their role in neoplasia. Cancer 55:2324-2328, 1985 5. Huebner RJ, Todara GJ: Oncogenes of RNA tumor viruses as determinants of cancer. Proc Nat1 Acad Sci USA 64:1087-1094, 1969 6. Todaro GJ, Huebner RJ: The viral oncogene hypothesis: New evidence. Proc Nat1 Acad Sci USA 69:1009-1015, 1972 7. Bishop JM: Viruses, genes, and cancer: II. Retroviruses and cancer genes. Cancer 55:2329-2334, 1985 8. Rous P, Kidd JG: Conditional neoplasms and subthreshold neoplastic states. J Exp Med 73:365-372, 1941 9. Mottram JC: A developing factor in experimental blastogenesis. J Path01 Bacterial 56:181-188, 1944

10. Boutwell RK: Tumor promoters in human carcinogenesis, in DeVita VT, Hellman S, Rosenberg SA (eds): Important Advances in Oncology-1985. Philadelphia, PA, Lippincott, 1985, pp 16-27 11. Boutwell RK: Some biological aspects of skin carcinogenesis. Prog Exp Tumor Res 4:207-213, 1964 12. Edmondson HA, Henderson B, Benton B: Liver cell adenomas associated with the use of oral contraceptives. N Engl J Med 294:470, 1976 13. Hoover R, Gray LA, Cole P, et al: Menopausal estrogens and breast cancer. N Engl J Med 295:401-405, 1976 14. Jick H, Walker AM, Rothman KJ: The epidemic of endometrial cancer. Am J Public Health 70:264-267, 1980 15. Armstrong BK: The role of diet in human carcinogenesis with special reference to endometrial cancer, in Hiatt HH, Watson JD, Winston JA (eds): Origins of Human Cancer. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1977, pp 557-565 16. Miller JA: Carcinogenesis by chemicals: An overview. Cancer Res 30:559-576, 1970 17. Yamagiwa K, Ichikawa K: Experimental study of the pathogenesis of carcinoma. J Cancer Res 3:1-29, 1918 18. Miller EC: Studies of the formation of protein-bound derivatives of 3,4benzopyrene in the epidermal fraction of mouse skin. Cancer Res ll:lOO-108, 1951

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Carcinogenesis.

The rationale for identifying carcinogens and their mechanisms of action is twofold. First, carcinogens must be identified so they can be eliminated f...
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