The basis for bladder cancer development and progression is complex and involves genetic abnormalities. These abnormalities yield phenotypic changes that allow normal transitional cells to become cancerous and finally acquire the “malignant phenotype.”
Methods
The authors review the most common genetic alterations in bladder cancer and the molecular mechanisms and pathways involved in the conversion of normal transitional cell into malignant transitional cancer cells.
Results
There are several potential genetic changes of the urothelium that eventually cause bladder cancer initiation and tumor progression. Some of these alterations are also found in other malignancies suggesting that key common pathways exist in the development of cancer.
Conclusions
As the roles of certain genes or proteins are further elucidated, a better understanding of cancer development can aid in the prevention, diagnosis, and treatment of bladder cancer.
References
1.
Cancer Facts & Figures, 2000.Atlanta, Ga: American Cancer Society; 2000: 1–40.
2.
SkinnerD.G., LieskowskyG.Management of invasive and high-grade bladder cancer. In: SkinnerD.G., LieskowskyG., eds. Diagnosis and Management of Genitourinary Cancer.Philadelphia, Pa: Saunders; 1988.
3.
MessingE.M., YoungT.B., HuntV.B.Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations. Urology.1995; 45: 387–396.
4.
KadlubarF.F., BadawiA.F.Genetic susceptibility and carcinogen-DNA adduct formation in human urinary bladder carcinogenesis. Toxicol Lett.1995; 82–83: 627–632.
5.
ButlerM.A., IwasakiM., GuengerichF.P.Human cytochrome P450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci U S A.1989; 86: 7696–7700.
6.
RischA., WallaceD.M., BathersS.Slow N-acetylation genotype is a susceptibility factor in occupational and smoking related bladder cancer. Hum Mol Genet.1995; 4: 231–236.
7.
KaderlikK.R., KadlubarF.F.Metabolic polymorphisms and carcinogen-DNA adduct formation in human populations. Pharmacogenetics.1995; 5: S108–S117.
8.
BellD.A., TaylorJ.A., PaulsonD.F.Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GST M1) that increase susceptibility to bladder cancer. J Natl Cancer Inst.1993; 85: 1159–1164.
9.
RehnL.Ueber Blasentrumoren bei Fruchsinalbeitern. Arch Kind Chir1895; 50: 588.
10.
StadlerW.M.Molecular events in the initiation and progression of bladder cancer. Int J Oncol1993; 3: 549.
11.
ColeP., HooverR., FriedellG.H.Occupation and cancer of the lower urinary tract. Cancer.1972; 29: 1250–1260.
12.
LucasS.B.Squamous cell carcinoma of the bladder and schistosomiasis. East Afr Med J.1982; 59: 345–351.
13.
BadawiA.F.Molecular and genetic events in schistosomiasis-associated human bladder cancer: role of oncogenes and tumor suppressor genes. Cancer Lett.1996; 105: 123–138.
14.
StonehillW.H., DmochowskiR.R., PattersonA.L.Risk factors for bladder tumors in spinal cord injury patients. J Urol.1996; 155: 1248–1250.
15.
TamirS., TannenbaumS.R.The role of nitric oxide (NO) in the carcinogenic process. Biochim Biophys Acta.1996; 1288: F31–36.
16.
TuttleT.M., WilliamsG.M., MarshallF.F.Evidence for cyclophosphamide-induced transitional cell carcinoma in a renal transplant patient. J Urol.1988; 140: 1009–1011.
17.
FernandesE.T., ManivelJ.C., ReddyP.K.Cyclophosphamide associated bladder cancer: a highly aggressive disease. Analysis of 12 cases. J Urol.1996; 156: 1931–1933.
18.
TravisL.B., CurtisR.E., GlimeliusB.Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst.1995; 87: 524–530.
19.
CohenS.M., GarlandE.M., St. JohnM. Acrolein initiates rat urinary bladder carcinogenesis. Cancer Res.1992; 52: 3577–3581.
20.
KhanM.A., TravisL.B., LynchC.F.p53 mutations in cyclophosphamide-associated bladder cancer. Cancer Epidemiol Biomarkers Prev.1998; 7: 397–403.
21.
KaldorJ.M., DayN.E., KittelmannB.Bladder tumours following chemotherapy and radiotherapy for ovarian cancer: a case-control study. Int J Cancer.1995; 63: 1–6.
22.
KleinermanR.A., BoiceJ.D.Jr, StormH.H.Second primary cancer after treatment for cervical cancer: an international cancer registries study. Cancer.1995; 76: 442–452.
23.
NeugutA.I., AhsanH., RobinsonE.Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma. Cancer.1997; 79: 1600–1604.
24.
QuiltyP.M., KerrG.R.Bladder cancer following low or high dose pelvic irradiation. Clin Radiol.1987; 38: 583–585.
WatsonP., LynchH.T.Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer.1993; 53: 677–685.
27.
KramerA.A., GrahamS., BurnettW.S.Familial aggregation of bladder cancer stratified by smoking status. Epidemiology.1991; 2: 145–148.
28.
GoldgarD.E., EastonD.F., Cannon-AlbrightL.A.Systematic population-based assessment of cancer risk in first-degree relative of cancer probands. J Natl Cancer Inst.1994; 86: 1600–1608.
29.
KiemeneyL.A., MoretN.C., WitjesJ.A.Familial transitional cell carcinoma among the population of Iceland. J Urol.1997; 157: 1649–1651.
30.
HornE.P., TuckerM.A., LambertG.A study of gender-based cytochrome P4501A2 variability: a possible mechanism for the male excess of bladder cancer. Cancer Epidemiol Biomarkets Prev.1995; 4: 529–533.
31.
YuM.C., SkipperP.L., TaghizadehK.Acetylator phenotype, aminobiphenyl-hemoglobin adduct levels, and bladder cancer risk in white, black, and Asian men in Los Angeles, California. J Natl Cancer Inst.1994; 86: 712–716.
32.
BernsteinL., RossR.K., DeapenD.Cancer in Los Angeles County: A Portrait of Incidence and Mortality 1972–1987.Los Angeles, Calif: University of Southern California and the California Tumor Registry, Dept of Health Services, State of California; 1991: 60–61.
33.
RossR.K., JonesP.A., YuM.C.Bladder cancer epidemiology and pathogenesis. Semin Oncol.1996; 23: 536–545.
34.
KnowlesM.A.Molecular genetics of bladder cancer. Br J Urol.1995; 1: 57–66.
35.
ReznikoffC.A., BelairC.D., YeagerT.R.A molecular genetic model of human bladder cancer pathogenesis. Semin Oncol.1996; 23: 571–584.
36.
TsaiY.C., NicholsP.W., HitiA.L.Allelic losses of chromosome 9,11 and 17 in human bladder cancer. Cancer Res.1990; 50: 44–47.
37.
Cordon-CardoC., WartingerD., PetrylakD.Altered expression of the retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst.1992; 84: 1251–1256.
38.
XuH.J., CairnsP., HuS.X.Loss of RB protein expression in primary bladder cancer correlates with loss of heterozygosity at the RB locus and tumor progression. Int J Cancer.1993; 53: 781–784.
39.
GrossmanH.B., LiebertM., AnteloM.p53 and RB expression predict progression in T1 bladder cancer. Clin Cancer Res.1998; 4: 829–834.
40.
CoteR.J., DunnM.D., ChatterjeeS.J.Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res.1998; 58: 1090–1094.
41.
HabuchiT., OgawaO., KakeniY.Allelic loss of chromosome 17p in urothelial cancer: strong association with invasive phenotype. J Urol.1992; 148: 1595–1599.
42.
EsrigD., ElmanjianD., GroshenS.Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med.1994; 331: 1259–1264.
43.
SarkisA.S., BajorinD.F., ReuterV.E.Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol.1995; 13: 1384–1390.
44.
CoteR.J., EsrigD., GroshenS.p53 and treatment of bladder cancer. Nature.1997; 385: 123–124.
45.
GlickS.H., HowellL.P., WhiteR.W.Relationship of p53 and bcl-2 to prognosis in muscle-invasive transitional cell carcinoma of the bladder. J Urol.1996; 155: 1754–1757.
46.
KeenA.J., KnowlesM.A.Definition of two regions of deletion on chromosome 9 in carcinoma of the bladder. Oncogene.1994; 9: 2083–2088.
47.
KambA., GruisN.A., Weaver-FeldhausJ.A cell cycle regulator potentially involved in the genesis of many tumor types. Science.1994; 264: 436–440.
48.
WuQ., PossatiL., MontesiM.Growth arrest and suppression of tumorigenicity of bladder-carcinoma cell lines induced by the P16/CDKN2 (p16INK4A, MTS1) gene and other loci on human chromosome 9. Int J Cancer.1996; 65: 840–846.
49.
GonzalgoM.L., HayashidaT., BenderC.M.The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines. Cancer Res.1998; 58: 1245–1252.
50.
QuelleD.E., ZindyF., AshmunR.A.Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell.1995; 83: 993–1000.
51.
TaoW., LevineA.J.P19 (ARF) stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2. Proc Natl Acad Sci U S A.1999; 96: 6937–6941.
52.
MaoL., SchoenbergM.P., ScicchitanoM.Molecular detection of primary bladder cancer by microsatellite analysis. Science.1996: 271; 659–662.
53.
SteinerG., SchoenbergM.P., LinnJ.F.Detection of bladder cancer recurrence by microsatellite analysis of urine. Nat Med.1997; 3: 621–624.
54.
MourahS., CussenotO., VimontV.Assessment of microsatellite instability in urine in the detection of transitional-cell carcinoma of the bladder. Int J Cancer.1998; 79: 629–633.
55.
CoombsL.M., PigottD.A., SweeneyE.Amplification and over-expression of c-erbB-2 in transitional cell carcinoma of the urinary bladder. Br J Cancer.1991; 63: 601–608.
56.
MellonJ.K., LunecJ., WrightC.C-erbB-2 in bladder cancer: molecular biology, clinical correlation with epidermal growth factor receptors and prognostic value. J Urol.1996; 155: 321–326.
57.
CzerniakB., DeitchD., SimmonsH.Ha-ras gene codon 12 mutation and DNA ploidy in urinary bladder carcinoma. Br J Cancer.1990; 62: 762–763.
58.
FontanaD., BellinaM., ScoffoneC.Evaluation of c-ras oncogene product (p21) in superficial bladder cancer. Eur Urol.1996; 29: 470–476.
59.
HirataY., OrthD.N.Epidermal growth factor (urogastrone) in human fluids: size heterogeneity. J Clin Endocrinol Metab.1979; 48: 673–679.
60.
MessingE.M., Murphy-BrooksN.Recovery of epidermal growth factor in voided urine of patients with bladder cancer. Urology.1994; 44: 502–506.
61.
MessingE.M., HansonP., UlrichP.Epidermal growth factor — interactions with normal and malignant urothelium: in vivo and in situ studies. J Urol.1987; 138: 1329–1335.
62.
RaoJ.Y., HemstreetGP3rd, HurstR.E.Alterations in phenotypic biochemical markers in bladder epithelium during tumorigenesis. Proc Natl Acad Sci U S A.1993; 90: 8287–8291.
63.
TheodorescuD., LaderouteK.R., CalaoaganJ.M.Inhibition of human bladder cancer motility by genistein is dependent on epidermal growth factor receptor but not p21ras gene expression. Int J Cancer.1998; 78: 775–782.
64.
MessingE.M.Clinical implications of the expression of epidermal growth factor receptors in human transitional cell carcinoma. Cancer Res.1990; 50: 2530–2537.
65.
LipponenP.K., EskelinenM.J.Reduced expression of E-cadherin is related to invasive disease and frequent recurrence in bladder cancer. J Cancer Res Clin Oncol.1995; 121: 303–308.
66.
BringuierP.P., UmbasR., SchaafsmaH.E.Decreased E-cadherin immunoreactivity correlates with poor survival in patients with bladder tumors. Cancer Res.1993; 53: 3241–3245.
67.
ShimazuiT., SchalkenJ.A., GiroldiL.A.Prognostic value of cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120cas) in bladder tumors. Cancer Res.1996; 56: 4154–4158.
68.
LiebertM., WashingtonR., WedemeyerG.Loss of co-localization of alpha 6 beta 4 integrin and collagen VII in bladder cancer. Am J Pathol.1994; 144: 787–799.
69.
FolkmanJ., ColeP., ZimmermanS.Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann Surg.1966; 164: 491–502.
BochnerB.H., CoteR.J., WeidnerN.Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst.1995; 87: 1603–1612.
72.
GuirguisR., SchiffmannE., LiuB.Detection of autocrine motility factor in urine as a marker of bladder cancer. J Natl Cancer Inst.1998; 80: 1203–1211.
73.
KormanH.J., PeabodyJ.O., CernyJ.C.Autocrine motility factor receptor as a possible urine marker for transitional cell carcinoma of the bladder. J Urol.1996; 155: 347–349.
74.
LockeshwarV.B., ObekC., SolowayM.S.Tumor-associated hyaluronic acid: a new sensitive and specific urine marker for bladder cancer. Cancer Res.1997; 57: 773–777.
75.
GrossfeldG.D., GinsbergD.A., SteinJ.P.Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst.1997; 89: 219–227.
