Document aDv20N1EQQgxZb7e8zdRdRkkM

Etiology of Bladder Cancer Tomoyuki Shirai SINCE the surgeon Dr R ~ h n ' ~f'irst suggested in 1895 a role for certain chemicals in the etiology of bladder cancer. this is historically the neoplastic disease most strongly linked to occupational and environmental exposure to chemicals. Subsequently. several chemical carcinogens that could be responsibie for human biadder cancer in particular groups of people have been identified. However, in many cases no obvious chemical carcinogen involvement can be found to explain cancer development. although factors such as cigarette smokmg, coffee drinking, use of analgesics. artificial sweeteners. bacterial and parasitic injections, bladder calculi. and anticancer chemotherapeutic agents have been indicated as causally related. In general, bladder cancer develops predominantly in males (two to five times more frequently in men than in women). No clear explanation has been made for this sex differences. By means of molecular biological approaches, it has been shown that carcinogens produce lesions in the genome of urothelial cells that initiate the process of carcinogenesis. Multiple lesions in the genome are required to cause complete malignant transformation of cells. and abnormalities of chromosomes, as well as induction of oncogenes and deletion of cancer suppressor genes, have all been shown to play possible roles. This review describes the etiological factors thought to be involved in bladder cancer development and general concepts in carcinogenesis. OCCUPATIONAL EXPOSURE Bladder cancer is the first human malignancy that was speculated to be related to systemic exposure to chemical(s) in the working place. Thus. after Rehn first described three cases of bladder cancer in workers in the German chemical dye industry, pointing out a possible causal relationship. similar reports appeared in Switzerland and England in the early 1900s. This provoked large numbers of investigations on occupational hazards, but the available data now indicate that the risks are not of general importance because the proportion of people exposed to individual factors at work is low.' Nevertheless, recent studies have estimated that between 2 1% and 23%of bladder cancers in Caucasians and 27% in nonwhites are occupationally related.' Similarly. it has been es- timated that occuvational exposure accounts for one fourth to on: third of bladder cancer cases in the United state^.^ The latent period may be as long as to 50 years4 Hueper et a14 demon- strated in 1938 that when fed to dogs. the indus- trial arylamine 2-naphthylamine could induce bladder carcinomas identical to human lesions. Contrary to original suspicions. however, aniline itself did not cause the disease. In the early 1950s Case and his associates performed an epiderni- oiogica~investigation of bladder cancers in work- ers in British chemical industries and found that arylamine-exposed individuals had a 30 times greater risk than did the general population. The average latent period for the development of bladder cancer was about 18 With se- lected exposure circumstances, as many as 100% of exposed workers developed bladder cancer.6 benzidine and 3-naphthylamine being implicated as especially potent human bladder carcino- gens.'.6 At present. both compounds are classified as human-bladder carcinogens' (Table 1). The low risk af bladder carcinogenesis by l-napli- thylamine is considered to be caused by contam- ination with ?-naphthylamine. In 1955 a close association between 4aminobiphenyl exposure and an increased risk of bladder cancer devel- opment was also reported from clinical tindings.' Thus. by the mid- 1950s, conclusive evidence was available implicating at least three industrial ar- ylamines as potent human-bladder carcino- Seminars in Urology, Vol XI, No 3 [Augustl, 1993: pp 1 13- 126 113 - 114 TOMOYUKI SHlRAl Table 1. Carcinogens for Which There is Evidence of Urinary Bladder-Cancer Induction in Humans Chemicals Induction of Bladder Cancer in Experimentol Animals 4-Ammobiphenyl Benzidine 2-Naphthylamine Cyclophosphamide N,N-Bis(2-chloroethy1)-2naphthylamine Phenocetin Mouse, dog, rabbit - Hamster, dog, monkey Rat - P:r I n 1975. it was shown that about 83% of hair dyes contain mutagenic aplamines and arylnitro compounds." One of these. 2.4-diaminotoluene was demonstrated to induce liver and mammary gland tumors in rats whereas p-cresidine (?-methoxy-5-methylaniline). was found to be a bladder carcinogen in both rats and mice.' Similarly. 4.4'm e t h y l e n e - b i s ( ~ - c h l o r o a n i l i n z ~ ~ ~ l O CusAed) ,as a curing agent for epoxy resins since the early 1950s, was shown to cause bladder carcinomas in dogs.'? Another agent. 3.3'-dichlorobenzidine, used in the dyestuffs industry for nearly 40 years and more recently used as a curing agent for polyurethane elastomers was also demonstrated to be a bladder carcinogen in dogs and rodents." Thus. human exposure to aplamines is considered an important causative factor for bladder carcinoma development. TOBACCO SMOKING . .. . ,. . that cigarette smoke 'contains a number 'of car- cinogenic nitroso compounds and many apl- amines. such as '-naphthylamines. toluidines. and 4-aminobiphenyl. Table 7 summarizes data on the concentration of arylamines in smoke from air-cured and flue-cured tobaccos'3 smoking the former type entailing exposure to a 2 to 2.3 times higher dose ofaqlamines. [n fact. there are three reports suggesting that air-cured tobacco is more carcinogenic for the bladder than flue-cured tokxco.!.'.'' AI!hough a lranety cjf chemicals in cigarette smoke are DiVA reactive in the urinary bladder epithelium, some may increase prolif- erative response in the bladder epithelium as ev- idenced by hyperplasias in cigarette smokers.'' This affect of cigarette smoke may exert an en- hancing effect on bladder carcinogenesis. SPECIFIC ENVIRONMENTAL CHEMICALS .C-.-lmiriohiphen~*i As mentioned above. the data on both occupational exposure and cigarette smoking strongly suggest that arylaminzs play important roles in human bladder carcinoma development. Among the difftrent arylamines that may be involved. the aromatic amine 3-aminobiphenyl (4-.4BP) must be taken into consideration. because it is experimzntally one of the most potent bladder Table 2. Amounts of Aromatic Amines in Condensotes of Air-Cured and FlueCured Tobaccos There is substantial evidence supporting a re- ng per Cigarette lationship between cigarette smoking and development of bladder cancer. with epidemiological studies showing that cigarette smokers have up Aromatic Amines Air Cured (France) Flue Cured (USA) to a fourfold higher incidence than nonsmok- . ers.13'15 The- association of smoking with bladder Aniline cancer holds for both s e x s and has been observed in many diff'erentgeographical areas of the USA. 0-Toluidine M-Toluidine P-Toluidine 102 32.2 15.3 13.5 364 162 30.4 333 Europe, and Japan. Similar results have been ob- 2-Ethylaniline 2,6-dimethylanlline 14.9 54.2 tained in both case-control studies"-'7and followup studies.'"'' The risk correlates with the number of cigarettes smokzd. the duration ofsmoking. and the degree of inhalation of the -2.5-Dimethylaniline 3-Ethyloniline 2.4-dimethylaniline 4-Ethylaniline - 2.3-dimethylaniline 1-Naphthylamine 2-Naphthylamine 19.1 14.0 7.8 4.3 1 .o 87.2 56.7 27.3 2.5 1.7 exsmokers having a reduced incidence of bladder 2-Aminobiphenyl 1.8 3.0 cancer as compared with current smokers.'* Al- though an estimated one third of bladder-cancer cases may be related to cigarette smoking.?-',.-1,- the 3-Aminobiphenyl 4-Aminobiphenyl 2-Methyl- 1-naphthylamine 2.7 5.0 2.4 4.6 5.8 3.6 specific chemical car_cinogcns responsible have not been identified. Hwtever. it has to be noted Note. Mainstream smoke condensates were analyzed. Data from Potrianakos C, Hoffmann 0.'' .. . ., . .. . I ETIOLOGY OF BLADDER CANCER . . . carcinogens and because the urinary-bladder . mucosae of cigarette smokers contain 4-ABP- DNA adducts identical to"those found in the bladder epithelium of dogs exposed to 4-amin~biphenyl.'~."A known human and mousebladder carcinogen. it is present in tobacco smoke," and is a probable ubiquitous environmental contaminant3' because it has been detected in the blood of individuals with no obvious chemical exposure. .4role for I-.ABP has been stressed by many investigator^.".'^ and increased exposure to cigarette-derived 4-ABP cleariy cor-.; relates with an increased incidence of bladder ~ancer.".'~Cessation of smoking is associated with a dramatic drop in the risk of cancer development'"^'" irrespective of the type of tobacco, air cured or flue cured. strongly suggesting that tobacco smoking acts partly as a tumor promoter in bladder carcinogenesis. N-Acetylation has been demonstrated to be involved in deactivation of some arylamines. including 4-ABP, and this reaction is mediated by N-acetyltransferase. Human populations show a characteristic genetically based polymorphism for the activity of this enzyme. with about one half of the subjects being "slow" acetylators and the other half "fast" acetylators. The slow acetylator thus possesses a lower capacity for detoxification as compared to the fast one. Lower et ai3` were the first to recognize the role of acetyltransferase phenotype in variable susceptibility to bladder cancer: they fotind patients from an urban population who were also phenotypic slow acetylators to be at increased risk of suffering from the disease. Cartwright et al" demonstrated that the proportion of slow acetylators was 57% among 207 controls and 67% among I 1 I bladder cancer cases. This proportion, however. was markedly increased when cancer cases were restricted to an occupationally exposed group (22.of 23 were slow acetylators, all suffering from transitional-cell carcinomas. The one exception of a fast acetylator had, in contrast, an adenocarcinoma). Thus the proportion of slow acetylators in occupational exposure cases was virtually 100%. this value being the highest reported in the literature. Other hospital-based case-control investigations of bladder cancer have been reported in which methods used for phenotyping were based on metabolism of sulfadimidine or sulfamethazine." Data from I 1 different places showed that there were no site-dependpt differences in the 115 /.; ' proportion of slow acetylators and that. overall. a 30% to 50% increase over general population `IeGelswas demonstrated for this proportion by bladder cancer patients. There are also data clearly demonstrating that the concentration of 4-ABP-hemoglobin adducts is higher in slow acetylators." With regard to the biochemical mechanism underlying the association between the slow-acetylator phenotype and an elevated risk of bladder cancer. the possibility of reduced detoxification dexrves particular consideration. .4nimal modeis ..ilgest that metabolic conversion of carcinogenic arylamines to N-acetyl derivatives represents a deactivation step elevated in phenotypic rapid acetylators. and thus slow acetylators would be expected to suffer more exposure to active carcinogenic species. Thus would explain the excess bladder cancer ca~es.~`.A'~rylamines are also metabolized by additional acetyltransferase pathways such as that catalysed by O-acetyltransferase. whose activity has also been associated with a polymorphic inheritance pattern." .A series of mutagenic and carcinogenic heterocyclic amines have been identified as foodpyrolysis products formed during the coolung or broiling of meat and fish." Of the variety of organs found to be their targets in rodents. the most common sites of tumor induction are the liver m d inrextinr. Particular attention has bcen paid to 2-amino- 1-methyl-6-phenylimidazo[4,jbjpyridine (PhIP)because it is the most abundant heterocyclic amine produced in cooking processes and it induces rat colon and mammary carcinomas, both of which are very common malignancies in populations who consume a large amount of meat. Of interest to this review, 3amino- 1-methyl-5 H-pyridol[4,3-b]indoI (Trp-P7) has recently been shown to induce bladder tumors in rats." In this context. it is important that cigarette smoke has also been reported to contain several mutagenic and carcinogenic heterocyclic amines including PhIP and Trp-P-2.""5 as well as the 4-XBP described above. The amounts of these heterocyclic amines generated were mea- sured to range from 0 . 3 to 160 ng/cigarette. TrpP-2 was reported to be present at levels of 0.82 to 1. I ng per cigarette. with a mean value of 0.95 ng/cigarette. Because carcinogenic heterocyclic amines are produced from meat and fish during 116 TOMOYUKI SHlRAl cooking, the fact of their presence in cigarette smoke suggests that they are also formed though combustion of tobacco. In fact. several heterocyclic amines have been found to be present in various environmental components such as airborne particles, rain water. cigarette smoke-polluted indoor air, and diesel exhaust particles.'6 These findings imply that carcinogenic heterocyclic amines in food and cigarettes could well be causative factors for bladder cancer in man. N-?iiiroso CornpoLinds Occupational hazards of Y-nitro-N-methylurethane and dimethylnitrosamine were early recognized by Wrigley4' and Barnes and Msgee,4s respectively. Extensive animal experiments have subsequently shown that nitrosamines produce many kinds of tumors in a variety of animal spe- cies. Under specific conditions. N-containing amines and amides may undergo N-nitrosation to yield N-nitroso compounds.'9 Furthermore, endogenous formation ofnitrosamine in the acid stomach from normal dietary intakes of nitrite and amino compounds has been demonstrated.'' Thus humans are exposed both to naturally oc- cumng and endogenously produced N-nitroso compounds. An important point regarding N- nitrosamines is that they have multispecies and multiorgan targets. a property shared by most other human carcinogens identified in the Inter- national Agency for Research on Cancer (IARC) monograph^.^' The cellular and molecular dam- age produced by nitrosamines is virtually iden- tical in animal and human tissues" and time- dose animal studies performed by Druckrey et ai5' indicate that long-term or lifetime exposure to even low levels of certain carcinogenic nitro- samines may represent a cancer risk to man. Concerning urinary bladder carcinogenesis, animal experiments have shown that many ni- trosamines exert carcinogenicity in this organ of dogs and Recently. it was found that endogenous nitrosation could also be mediated by bacteria" and by macrophages6' in infected or inflamed organs. It was reported that as many as 30%of the strains of microorganisms isolated from human achlorhydric gastric juice and about 90% of strains from urinary tract infections pos- sess nitrosating enzymes.6' and Ohshima et a162 aild Tricker et d3detected N-nitrosamines in infected urinary bladders. Bacteria that can cat- alyze N-nitrosamine formqion and reduce ni- trates to nitrites could clearly be responsible for production of N-nitroso compounds in situ in individuals with urinary-tract infections. In fact, high levels of nitrosamines are detected in bacteria-infected bladders of patients suffering from Schistosoma hematobium as described below. Available data therefore point to a probable important role for nitrosamines in the etiology of urinary bladder cancer. ,Iledicines .4nal,ae~icagmrs. A possible relationship between analgesic abuse and the development of malignant neoplasms in the urinary tract was first pointed out in Swedenh' This possibility has now also been recognized in other countries. and the occasional development of bladder carcinomas was also mentioned as a result of phenacetin abuse by the I.4RC.65Phenacetin is normally used alone or in combination with aspirin and caffeine: The usual dose is 300 mg, taken four to six times per day to give a total of no more than 7.1 g per day.66Bengtsson et alo7surveyed 62 patients with phenacetin-related pelvic tumors and estimated average phenacetin consumption to be about 9 kg with a range from 1.5 kg to 2.7 kg. Over a long period (more than 10 years), the exposure is thus considerable and an increased nsk of bladder carcinoma development under these conditions appears clear.68Phenacetin was evaluated to have sufficient evidence for carcinogenicity to humans as analgesic mixtures." It has a chemical structure similar to that of aniline dyes and although it is itself not nephrotoxic, most of its metabolites and some related compounds have been found to cause kidney damage.69 N-Hydroxy phenacetin. formed by hydroxylation of this arylamide, induces liver carcinomas in rats at high incidence but only few tumors of the urinary tract. probably because it is nearly all metabolized in the liver and very little reaches the kidney. In 1979, Isaka et al" first showed experimentally that phenacetin could induce transitional cell carcinomas of the urinary tract and carcinomas of the nasal cavity of Sprague-Dawley rats. However, Xakanishi et al" had earlier reported that phenacetin could promote nitrosamine-initiated F344 rat urinary-bladder carcinogenesis. Cyclophosphamide. Cyclophosphamide is an alkylating agent that has been used in the treatment of malignant neoplasms, and particularly, ETIOLOGY OF BLADDER CANCER :... . . . . ,. lymphoproliferative and"mye1oproliferative dis- eases. It is acutely toxic to the bladder. mucosa ' . and produces marked cellular abnormalities in the epithelium. Clinical administration of cyclo- phosphamide is associated with various degrees of hematuria. In 1971 Worth reported the first two cases of bladder cancer related to cyclophosphamide therapy." Since that time. at least 39 urinarytract neoplasms following chemotherapy with cyclophosphamide have been described in the literature." Hicks" described cyclophosphamide to act with N-methyl-N-nitrosourea as a cocar- cinogen for induction of bladder cancer in rats and Schmahl and Habs" later provided the first demonstration that administration of cyclophos- phamide could induce bladder carcinomas in rats. Patients treated with cyclophosphamide have an up to ninefold increased risk of bladder- cancer development, although a causative relationship has not yet been formally demonstrated in case-control epidemiological st~dies.'T~ he cumulative risk is 3.5% after 8 years and 10.7% after 12 years.76Most of the tumors involved are of transitional-cell type and present as muscleinfiltrating lesions at the time of diagnosis." The latent period for neoplasia related to this drug is therefore relatively short, ranging from 6 to 13 years. IARC has evaluated cyclophosphamide as in the group 1 ~ategory.'~ Cyclophosphamide is also an immunosuppressive agent, this effect being now well recognized as a contributing factor. It is unclear whether cyclophosphamide-induced urothelial malignancies are due to its immunosuppressive or inherent carcinogenic properties but probably the two influences work cooperatively. Of four known metabolites of cyclophosphamide, acrolein and phosphoamide mustard have been demonstrated to bind to DNA78and acrolein is known to be responsible for its bladder toxicity." It is also believed to be the prime cause of the associated urothelial malignancies."." 2-Mercaptoethane sodium sulfonate (Mesna) was first used successfully to prevent cyclophosphamide-in- duced hemorrhagic cystitis in 198-4," binding to the double bond of the acrolein molecule and thus detoxifying the metabolite. Intravenous administration of Mesna significantly alleviated the processes of ulceration and inflammation in the bladders of rats given cyclophosphamide," and SchmBhl and Habs7*further show that its appli- 117 cation can reduce induction of bladder carcinoma . by t h s ctinicdly-important agent. Forced diuresis has also been shown to be associated with a significant decrease in the incidence of hemorrhagic cystitis in patients on a high-dose regimen of cyclophosphamide." N , N -Bis(2-chloroethyl)- 2 - naphthylamine (Chlornaphazine). Chlornaphazine was used as a therapeutic agent for polycythemia in mid 1990. It was reported that among 6 1 patients receiving chlornaphazine, 13 developed bladder carcinomas, and 8 had abnormal urinary cytology. Invasive carcinomas were observed in 4 of 5 patients treated with a cumulative dose of 200 g or more.s3 Although no evidence exists for bladder carcinogenicity to rodents. it was <valuated as a human ~arcinogen.'~ Tryptophan For many years, tryptophan and its metabolites have been suspected as being etiologcal agents in bladder carcinogenesis. For example, bladdercancer patients were reported early to have increased levels of urinary tryptophan metabolites.'` and tumor recurrence rates are more frequent in patients with elevated excretion of metabolites derived from this amino a ~ i d . ~ ' . * ~ Although administration of tryptophan to experimental animals does not induce bladder cancer, it was demonstrated that dietary tryptophan or its metabolites could enhance bladder carcinogenesis.".'a However. more recent studies suggest that endogenous tryptophan metabolism does not contribute significantly to the development of bladder cancer.59 On the other hand, a pyrolysis product of tryptophan. Trp-P-2, is currently known to induce bladder carcinoma in rats" as described in a previous section. It can be formed during cooking of'meat or fish4' and is strongly mutagenic in Salmonella typhimnrium. DIETARY FACTORS `4rtifrciai Sweeteners Artificial sweeteners, particularly saccharin and cyclamate, have been shown to act as bladder carcinogens in rodents when given in very large doseswThe conclusion of complete carcinogenic potential is. however, controversial because of the extremely high exposurc !evels, and ir has no`w been clearly demonstrated that both saccharin and cyclamate are strong tumor promoters in the 118 TOMOYUKI SHlRAl bladder. .Recent extensive studies by Fukushima et a19'.y2showed that the promoting potential of investigations have also shown that bacterial in- sodium ascorbate for rat u r i n a F bladder carcinogenesis is because of elevation of urinary pH 'fection in the urinaq'trJct promotes bladder car- cinogenesis in ratsl"J.'Dacnc I.n this case a hyper- and Na+ concentration in combination. They plastic response of the bladder epithelium is found that many compounds that enhance tumor thought to be responsible. Hdwever. the exact development in the bladder share this character" and in ail cases of saccharin experiments. the Nasalt form had been used. It was later confirmed that sodium saccharin. but not the saccharin acid form. exerts promoting potential for bladder carcinogenesi~.~In' this context. it is of interest that cyclamate is also given as the sodium salt. Casecontrol epidemiological studies in humans. however, have provided little evidence for increased risk of bladder cancer in consumers of artificial .A proliferative and neoplastic response following oral administration of high doses of sodium saccharin has been seen only in the rat, generally with considerably greater effects in males than in females." From the mechanistic view point. Ellwein and Cohen" therefore concluded that sodium saccharin has little effect on human urothelial cells at even the highest levels of human consumption. mechanisms whereby bladder cancers are induced in chronically infected human bladders is unclear. 4 s discussed in ihe section on nitrosnmines. in situ formatitin of carcinogenic nitroso compound(s\ mediatd b y bacteria could play an important role. In regions of North .Africaand the Middle East. where infection with SiJiistu.romu hrtnarobiim. a water-borne parasite. is endemic (schistosomiasis, bilharziasis). there is a very high incidence of bladder cancer. Known to have a lethal outcome despite aggressive surgical and chernotherapeutic treatment. bilharziasis-associated bladder cancer is characterized by a predominance of squamous-cell carcinoma^.'^"^'^' El-Bolkainy et al histopathologic~llyreviebved. a series of 1095 Egyptian bladder-carcinoma patients treated by radical cystectomy and found that in 83.4% of cases. specimens were positive for schistosome Coy& and Tea Drinking e g s . and tumors developed at 3 younger age (46.7 5 Coffee drinking has been implicated by some studies into the etiology of bladder years) in this group than in the 17.6% of eggnegative cases (53.2 years). However. they found An increased risk of bladder cancer has also been no differences in the frequencies of various tumor reported in association with tea drinking.'* Nev- stages or llmph-node metastases between the two ertheless. a recent review by IARC" stated that groups. The etiolog>,of bladder cancer in patients there is no consistent association in descriptive suffering from bilharziasis presumably involves studies between coffee intake and cancer risk and many factors including carcinogen exposure and that in case control studies. the observed weak mechanical irritation by eggs. Secondary bacterial positive relationship might be due to bias. In ad- infection is once again suspected as an important dition no association was concluded for tea con- f a ~ t o r . ' ~th' e most commonly identified organ- sumption. isms being E coli-Sraph~,lococci,and P.yezido- monus. . - BLADDER INFECTION .. Seventy of bacterial infection correlates with A number of epidemiological and experimental studies have convincingly indicated that urinary tract infection is a strong risk factor for the elevation of urinar2; d-glucuronidase, which may activate potential carcinogenic compounds excreted from the liver as glucuronides."' Further- development of bladder The ma- more. the bacteria found can convert nitrate to jority of bladder cancers linked with exposure to chemicals. as reviewed above. are transitional cell nitrite. resulting in production of carcinogenic nitrosamines by reaction with amines.".'I and carcinomas with a variable biological potential. the appearance of urinary nitrite also appears de- In contrast. the cancers related to chronic urinary pendent on the secerity of bacterial infection. In infection are generally deeply invasive squamouscell carcinomas that show a poor prognosis. This fact. four nitrosamines have been identified in the urine of bilharzial patients."'."' and studies type of cancer has been reported to occur in pa- in Egypt showed the amounts of nitrosamines tients with spinal cord injury,who inevitably de- extracted from chemically nitrosated urine of ETIOLOGY OF BLADDER CANCER 119 ' bilharzial patients with or without bladder cancer and they speculated that the diet rich in protein, to be 70 times higher than in controls."' as in Western countries. is a risk factor."' Vitamin A deficiency may be an additional factor related to development of squamous cell GENETIC FACTORS metaplasia, and serum levels of $-carotene and From the above it is clear that the etiology of vitamin A were demonstrated to be lower in bil- bladder cancer involves environmental factors. harzial patients with squamous cell carcinoma In addition. it has already been noted that a ge- than in those with transitional cell carcinoma."' netic predisposition to bladder cancer may exist. Urinary calculi. which are commonly asso- The incidence of cancer of the bladder in different ciated with urinary tract infections. have also areas of the world varies almost ninefold in males, been linked to urothelial malignancies. In rodents and 190-fold in females. Although this interna- calculi can induce severe urothelial hyperplasia tional variation is pracrisally the smallest among and promote bladder carcinogenesis.' 16-' and the common cancers.'" race. sex. and geograph- their presence alone can result in development ical differences within the United States have also of bladder carcinomas in rats when exposure is been documented.'" S<hulte'30has reviewed the prolonged."* Epidemiologically. Kantor et allm literature on the influence of genetic factors in similarly found that bladder stones present an bladder cancer. and summarized findings into increased risk for bladder cancer. Furthermore, four categories: ( 1) familial aggregation; (2) ge- urothelial hyperplasia and dysplasia are com- netic polymorphism; (3) N-acetyltransferase monly observed in association with stones."' phenotype: and (1)activated oncogenes and URINE chromosomal changes. He stated that a role for genetic factors could not be conclusively ascer- It was recognized early that the urine is im- tained, but he proposed that two different patterns portant for the development of bladder cancer of genetic involvement might be identified. One because it acts as a medium of exposure to car- is the Mendelian pattern of autosomal dominant cinogenic substances. '2*'21 The significance of inheritance observed in a very small number of urine-borne, rather than blood-borne, effective cases. and the other is the multifactorial pattern metabolites of bladder carcinogens was also involving genetic and environmental interaction. shown by Ito et al,"' who showed that unilateral Since Fraumeni and Thomas'" published the ureter ligation resulted in induction of renal pel- first report of familial occurrence of bladder can- vic cancers, that normally do not develop, at the cer in a man and his three sons, many cases of site of the ligation. Furchermore, Hashimoto and bladder-cancer development in d i e r e n t family K i t a g a ~ a " ~reported that in vitro neoplastic members have been documented.'30Familial ag- transformation of rat urothelial cells by nitrosa- gregation is however not necessarily confirmation mine required the presence of urea in the tissue- of a genetic etiology but may be also caused by culture medium. Oyasu et subsequently shared environmental factors or even freak ran- demonstrated the significance of urine for car- dom distribution. Nevertheless. Punilo et ai"' cinoma development in a heterotopically trans- suggested that familial bladder cancer occurs planted urinary bladder system. They have found rather more commonly than had been earlier that a specific factor is responsible for urine-pro- thought, from their data on 13 cases of bladder motion of bladder carcinoma development, and cancer that occurred during a ?-year period in recently, epidermal growth factor was shown to six unrelated families. An excess of the A gene present in the urine."' of the A B 0 blood group in bladder-cancer cases Kakizoe et ai found that of 2. I amino acids, L- was demonstrated by Herring et who have leucine and L-valine increased Concanavalin A also investigated human leukoc]iteantigen (HLA) agglutinability of isolated rat-bladder cells in an polymorphism and found two HLA genes, B5 in vivo-in vitro system, suggesting that both are and Cw 1,to be increased. However, other details possible tumor Subsequently they regarding any association between HLA and this demonstrated that dietary supplementation with neoplasia are not available to our knowledge. both amino acids promoted bladder-cancer de- As described in a previous section. phenotypic velopment in rats initiated with a bladder carcin- variation in N-acetyltransferase activity has been ogen, N-butyl-N-(4-hydroxybutyl) nitrosamine, found to be associated with bladder cancer, par- jf 1 i 1' 4 120 TOMOYUKI SHlRAl ticularly in workers elcposr.d to aromatic amines. with invasive growth has also been reponed by This is an autosomal rectssivt: trait and popula- Fujimoto et al.'. " and it has recently become clear tions can be divided into t\vo distinct phenotypes, that the kinds c mutations sustained in the p53 slow and fast acet>lators. The ratio between these tumor suppressor gene might retlect exposures to two varies among racial and ethnic groups and different environmental carcinogens. Spruck et Kadlubar et all-'" suggested that quantification of all"' h?ve compared the spectrum of mutations molecular adducts of aromatic amines might be in the tumor suppressor gene in the tumors of useful to test genetic susceptibility to bladder smokers and nonsmokers. to determine whether cancer. differences exist in the kinds of mut3tions in these The concept of cancer as a genetic disease re- two groups. There were no obvious differences sulting from genetic changes in somatic cells is in the types or positions of mutations seen. How- now well recognized. It is like!y that multiple le- ever. there was 2 high frequency of double mu- sions are required to cause malignant transfor- tations seen in smokers only. sugesting that cig- mation of any given cell. and bladder cancers arette smoke ma); act to increase the extent of demonstrate alterations in many kinds of onco- DNA damage. In the near future, these kinds of gene (mutation, over expression and deletion) as molecular approaches should help to disclose eti- with many other types of malignant tumor. Sev- ologically specific DNA changes within tumor eral oncogenes in the rus gene family have been suppressor genes that might give important clues investigated in bladder ~ 3 n c e r s . ~ ~Tjh. e" ~H-ras to the mechanisms by which chemicals or other oncogene was found to be activated in 7% to 17% agents induce bladder carcinogenesis. of human bladder cancer cases.133.138 A number Retinoblastoma (Rb) tumor suppressor gene of workers have demonstrated expenmentally- alterations have been frequently found in bladder induced bladder carcinomas to similarly contain cancerii8 and their role might also be important mutated or activated ras genes and show en- for neoplastic development in the bladder. hanced expression of pZ 1.13L).1'o The expression Understanding the molecular defects seen in of c-myc oncogene was found to correlate with human bladder tumors. and a delineation of the recurrence or invasion in superficial bladder roles of specific tumor suppressor genes is likely cancer. 'I to be achieved over the next few years. This mo- A role for tumor suppressor genes in the de- lecular approach will undoubtedly add very sig- velopment of human bladder cancer have re- nificantly to our understanding of the mecha- cently been proposed by several laboratories. nisms by which the urothelium becomes High frequencies of loss ofheterozygosiry (LOH) transformed during carcinogcnesis. of chromosomes 9q, 1 1p. and 17p have been observed in bladder c a r c i n o r n a ~ .L~O~H~ o~f~ ~ ~ GENERAL CONCEPTS IN CARCINOGENESIS chromosome 9 is seen in both low and high stage tumors whereas allelic losses of other chromo- itfLiltisrage Carcinogenesis somes seem to be associated with tumor pro- The concept of initiation and promotion gression. It has therefore been postulated that in- originally evolved from skin carcinogenesis activation of a tumor suppressor gene located on experimentsLJ9.'Sh0as now been expanded to chromosome 9 is an early event in the develop- cover carcinogenesis in many organs including ment bladder cancer."'"'" The isolation and the urinary bladder. The "initiation" is the first characterization of this tumor suppressor gene event of the carcinogenic process in which irre- are necessary to facilitate full understanding of versible or memorized genetic alteration(s) is in- this disease. duced in target cells by exposure to chemical or In contrast to the stage and grade independent physical agents. 4 chemical. physical. or biolog- loss of chromosome 9 in bladder cancers. losses ical agent that is capable of inducing such alter- of chromosomes 1 1p and 17p. where the p53 gene ations is termed an '-initiator" or "initiating" is located, are associated with high grade, high agent. Repeated exposure induces additive effects stage tumors.li3 The p j 3 tumor suppressor gene in such genetic alterations. Initiated cells, how- in human bladder cancers has been shown to ever, are not readily identifiable. For the initiation contain frequent point mutations in the retained event, cell replication could facilitate fixation of p j 3 allele. '"j Association_of pj3-gene mutations genetic alterations (DNA damage). Spontaneous ETIOLOGY OF BLADDER CANCER 121 -,./v<.e:. ,..., .*: ~..,.,, . . # gr,'fortuifoustxiburrenci.ii . .. ., i . ( . . practically ` k t t o drive .the whole process, and play a role. It is unlikely that initiation alone pro- tumor development may occur without subse- ceeds to formation of frank tumors. quent administration of exogenous promoters, Promotion is the second-stage process in which because there are many endogenous promoting initiated cells grow clonally to form tumor factors or substances. Similarly. promoters could masses. The process usually requires repeated induce tumors without apparent application of exposure of cells to certain agents over long pe- an initiator. if they can stimulate growth of spon- nods. Biological characteristics of promotion are taneously-initiated cell populations. reversible increase in replication of the initiated Complete carcinogens can be categorized into cell population and reversible alterations in gene several classes. according to their abilities for ini- expression. Unlike initiators. promoters do not tiation and promot!on.'56 Some have strong ac- themselves directly react with the genetic mate- tivities in both initiation and promotion stages, 'rials. They exert more tissue and/or organ de- pendency than initiating agents" and continu- but some are strong initiators and weak promoters and vice versa. The overall carcinogenic ac- ous cell proliferation seems very important for tivity of a chemical. therefore, may depend on promotion."' Many. but not all. promoting the interplay between these activities. agents stimulate cell proliferation in target cells. Carcinogens can also be divided into two cat- Recently. the concept of multistage carcino- egories, genotoxic and nongenotoxic. although genesis has increasingly come to include pro- precise classification is sometimes difficult. Ge- gression in addition to initiation and promotion. notoxic carcinogens are DNA reactive. with or The progression was first proposed by F o ~ l d s ` ~ ~without dependency on enzymatic activation. who described it as the process of development Nongenotoxic (also called cpigenetic) agents have of malignant neoplasia that obtained higher de- reliable evidence of an inability to interact with grees of autonomy and malignancy. Earlier pro- genetic materials and exert other lunds of bio- motion included all processes until malignant logical effects that appear to be the basis for their tumor development. Progression is a relatively car~inogenicity.'~T'herefore. there is a wide va- late stage of the carcinogenic process in which riety of types of agents in this category with dif- genetic alterations such as oncogene activation, ferent modes of action. Many of them increase gene amplification in neoplasms associated with DNA synthesis, mitosis, and cell duplication increased growth rate. invasiveness. metastatic rates.'" Some of them, however, could induce potential and capability. morphologic character- DNA damage through indirect mechanisms, such `'`istics. and/or hormone responsiveness are in- volved. as producing oxygen r a d i ~ a 1 s . lB~e~cause genotoxicity is at least partly irreversible and is ad- Molecular biological approaches are revealing ditively accumulated, genotoxic carcinogens are roles for many lunds of genetic alteration generally effective for induction of tumors at low (changes in oncogenes and antioncogenes), re- doses, whereas nongenotoxic chemicals need high flecting the multistage nature of neoplasia. Sev- doses, reflecting the presence of a threshold level eral genetic alterations are generally required for to exert carcinogenicity. Strong promoters are malignant transformation. These alterations nongenotoxic carcinogens, as in the case of phe- . evoke heterogeneity in tumor morphology and nobarbital in the liver. Precise distinction behveen biology. promoters and nongenotoxic c3rcinogens is, Characterisrics of Carcinogenic .-lgents and Their `Wade qf.4ction however, sometimes difficult. If a promoter alone induced certain type of tumors with a statistical significance in a lifespan animal experiment. it The majority of known carcinogenic agents would of necessity be classified as a nongenotoxic possess the capacity for both initiation and pro- carcinogen. motion. They are termed "complete carcinogens'>152.155 and are capable of inducing DNA al- Direct genotoxic effects are the result of interaction of chemicals themselves or the interaction terations as well as cell proliferation. Chemicals of their electrophilic metabolites with DKA. that possess only initiating activity are termed Carcinogenicicy of chemicals that require bio- "incomplete carcinogens." .4 single or very short- transformation to yield electrophiles depends on term administration of complete carcinogen may activities of activating and/or detoxifyin,0 en- I 122 .I. . . . . . . zyme(s). which vary with organs. strains. species, and sex. These enzyme activities are furthermore easily influenced by many chemicals. nutrition. and other environmental factors. resulting in either inhibition or enhancement ofcarcinogenesis. .Additive or synergistic effects of two or more carcinogens are designated as "syncarcinogenesis." occumng when diferent agents acting on the same target organ are given together or in sequence. Another mode of carcinogenesis is cocarcinogenesis. by Lvhich cocarcinogen enhances the efectiveness (neoplastic conversion) of a carcinogen present at the same time. Promotion. in contrast. occurs subsequent to exposure to a carcinogen and only enhances neoplastic development of previously initiated populations. Hiiinnn Sirliarion Concepts of carcinogenic processes. including information relating to biological characteristics of each stage in tumor development. effective doses of carcinogens or modifying chemicals. species and/or organ specificities. and mode of interaction between two or more agents are essential in considering human cases. In the human bladder, initiation might occur because ofthe action of many kinds of genoto.uk chemicals and drugs. including aromatic amines. benzidine, Nnitroso compounds. and cyclophosphamide and phenacetin. Promotion will occur because ofexposure to aromatic amines. phenace?in. c).totoxic agents, chronic bladder infection. and mucosal injuries. Tryptophan metabolites may or may not be promoters. Cigarette smokes contains a variety of chemicals classified as genotoxic and nongenotoxic carcinogens and promoters. They might act synergistically and/or play a role in the cocarcinogenic mode. I t is important to note that many of the specific steps in carcinogenesis are controlled and modified by numerous endogenous and exogenous factors. Among the exogenous elements. nutritional factors are very much invoi ved. SUMMARY That the etiolog? of bladder cancer involves environmental factors is ne11 documented. Most chemical carcinogens probably affect the urothelial cells via their presence in the urine. A s an important cofactor. cell-proliferative activity may be increased by urinaq bladder infection. ;nitation by bladder stonz_sor through the action of TOMOYUKI SHlRAl 'A .van& of 'direct ikting chemicals or agents. Among the known c3usative factors; avoidable major ones are occupational exposure to certain chemicals such as benzidine and h m i n o b i phenyl. cigarette smoking. and bilharzial infection. which could be eradicated by a Combination of praziquantel. antihdminth therapy, education. and improvements i n scciai welfare. A n anticarcinogenic drug. cyclophosphamide. used as an imniunosuppressive agent also seems to be associated with a high risk of idiopathic induction of bladder cancer and ph) sicians should therefore pay particular attention to its diverse effects when considering its prescription. In contrast to the above. the consumption of coffee and tea containing artificial sweeteners is now thought unlikely to be a major risk. So far there is no good biochemical tool to predict individual esposure to bladder carcinogens/or re1atit.e risk of bladder-cancer development. 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