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ANNUAL
REVIEWS

9 December 2008

15:4

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Molecular Pathogenesis and
Diagnostics of Bladder Cancer
Anirban P. Mitra1 and Richard J. Cote1,2
Departments of 1 Pathology and 2 Urology, Keck School of Medicine and Norris
Comprehensive Cancer Center, University of Southern California, Los Angeles,
California 90033; email: amitra@usc.edu; cote r@ccnt.usc.edu

Annu. Rev. Pathol. Mech. Dis. 2009. 4:251–85

Key Words

First published online as a Review in Advance on
October 7, 2008

urothelial carcinoma, risk factors, cellular pathways, prognosis,
combined marker analysis

The Annual Review of Pathology: Mechanisms of
Disease is online at pathmechdis.annualreviews.org
This article’s doi:
10.1146/annurev.pathol.4.110807.092230
c 2009 by Annual Reviews.
Copyright 
All rights reserved
1553-4006/09/0228-0251$20.00

Abstract
Despite elaborate characterization of the risk factors, bladder cancer is
still a major epidemiological problem whose incidence continues to rise
each year. Urothelial carcinoma is now recognized as a disease of alterations in several cellular processes. The more prevalent, less aggressive,
recurrent, noninvasive tumors are characterized by constitutive activation of the Ras-MAPK pathway. The less common but more aggressive
invasive tumors, which have a higher mortality rate, are characterized
by alterations in the p53 and retinoblastoma pathways. Several diagnostic tests have attempted to identify these molecular alterations in
tumor cells exfoliated in the urine, whereas prognostic tests have tried
to identify aberrations so as to predict tumor behavior and identify therapeutic targets. The future of bladder cancer patient management will
rely on the use of molecular tests to reliably diagnose the presence of disease, predict individual tumor behavior, and suggest potential targeted
therapeutics.

251

ANRV368-PM04-11

ARI

9 December 2008

15:4

Annu. Rev. Pathol. Mech. Dis. 2009.4:251-285. Downloaded from arjournals.annualreviews.org
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252

Mitra

·

Cote

or a n gi o ge nes

m
Tu

Gene
regulation
Signal
transduction

Cell
growth

on

The incidence of UC is three to four times
higher in males than in females (2). The increased incidence of UC in men has been
attributed to environmental and dietary exposures, innate sexual characteristics (e.g.,

Cell
death

r ce ll i nv asi

RISK FACTORS FOR
BLADDER CANCER

Cell-cycle
regulation

mo

Relative risk: ratio of
the risk of disease
among the exposed
population to the risk
among the unexposed

Cancers of the urinary bladder present as
urothelial carcinoma (UC) or as transitional
cell carcinoma, squamous cell carcinoma, adenocarcinoma, and certain other rare subtypes
(1). Global estimates suggest that in 2002,
approximately 357,000 bladder cancer cases
were diagnosed and that approximately 145,000
patients succumbed to the disease (2). Based
on 2002–2004 estimates, 2.35% of the individuals born in the United States today will be
diagnosed with UC during their lifetime (3).
UC is the fifth most expensive cancer to treat,
accounting for $3.7 billion in direct costs (4).
There is strong evidence that the process
of malignant transformation of the bladder
urothelium is due to alterations in molecular
pathways that are otherwise responsible for the
maintenance of cellular homeostasis (5). Several key molecules and pathways that regulate
critical cellular processes have been identified
as important in the course of urothelial tumorigenesis and progression (Figure 1). These include five “intrinsic” processes that can respond
to external carcinogenic cues or become internally deregulated due to genetic alterations:
cell-cycle regulation, cell death, cell growth,
signal transduction, and gene regulation. Also
important are two “extrinsic” processes that
contribute to tumor maintenance and progression by interacting with stromal elements and
adjoining cells: angiogenesis and tumor cell invasion. Here we review the various risk factors
that can alter these processes, the impact of
these genetic and molecular alterations on tumor progression and prognosis, and how identification of these alterations can help in the
early diagnosis of UC.

Tu

UC: urothelial
carcinoma

is

INTRODUCTION

Figure 1
Aberrant cellular processes contributing to bladder
tumorigenesis. Malignant transformation of the
bladder urothelium involves alterations in five
intrinsic cellular processes (central pie) that can
respond to external carcinogenic cues or that can be
affected by genetic alterations. Tumor maintenance,
progression, and metastasis also depend on two
extrinsic processes, angiogenesis and invasion,
which regulate tumor interaction with stromal
elements and adjacent cells.

anatomic differences), urination habits, and
hormonal factors (1). High exposure to tobacco
smoke and occupational exposure to aromatic
amines, the two major environmental risk factors, also contribute to this effect. The disease
is more common in Caucasians than in African
Americans, Hispanics, and Asians (3). The risk
increases with advancing age, and most cases
are diagnosed in individuals between 65 and 84
years of age (6).
A variety of lifestyle choices, occupations,
dietary factors, drugs, urologic pathologies,
family histories, and genetic polymorphisms increase UC risk (Table 1). In the United States,
tobacco smoking is the most important risk
factor. The relative risk of UC development
in smokers is two to four times that of nonsmokers, and it increases with the number of
cigarettes smoked and the duration of smoking (7). Former smokers generally have a lower
risk of UC than do current smokers. Tobacco
smoke is rich in aromatic amines and other

ANRV368-PM04-11

Table 1

ARI

9 December 2008

15:4

Risk factors for bladder cancer

Risk factor

Mechanism of carcinogenesis

Primary cellular
process(es) altered

Strength of
association

Reference(s)

Lifestyle
Tobacco smoking

Exposure to carcinogens in tobacco
smoke, including aromatic amines,
hydrocarbons, and tar

Cell-cycle regulation,
gene regulation

Strong

7

Hair dye use

Exposure to aromatic amines

Cell-cycle regulation

Weak

10

Dyestuff manufacturing

Exposure to aromatic amines and aniline
dyes

Cell-cycle regulation,
gene regulation

Strong

1

Rubber manufacturing

Exposure to aromatic amines, aniline,
and o-toluidine

Cell-cycle regulation

Strong

14

Painting

Exposure to aromatic amines and aniline
dyes

Cell-cycle regulation,
gene regulation

Moderate

15

Leather processing

Exposure to aromatic amines

Cell-cycle regulation

Moderate

16

Printing

Exposure to aromatic amines and aniline
dyes

Cell-cycle regulation,
gene regulation

Weak

16

Hairdressing

Exposure to aromatic amines from hair
dyes and gels

Cell-cycle regulation

Weak

10

Aluminum smelting

Exposure to polycyclic aromatic
hydrocarbons

Cell-cycle regulation

Strong

17, 18

Asphalt paving

Exposure to polycyclic aromatic
hydrocarbons

Cell-cycle regulation

Inadequate

19

Firefighting

Exposure to aromatic amines and
polycyclic aromatic hydrocarbons

Cell-cycle regulation

Weak

20

Truck driving

Exposure to diesel exhaust

Cell-cycle regulation

Moderate

21

Chlorine and chlorination
by-products (in drinking
water)

Direct carcinogenic effect

Unconfirmed

Moderate

22

Arsenic (in drinking water)

Direct carcinogenic effect

Cell-cycle regulation,
signal transduction,
gene regulation

Strong

24

Coffee

Carcinogenic metabolites from caffeine
in the urine

Unconfirmed

Inadequate

27

Artificial sweeteners

Unknown in humans

Unconfirmed

Inadequate

29

Induction of DNA fragmentation

Gene regulation

Moderate

1, 30

Schistosoma haematobium

Exposure to toxins and N-nitrosamines

Gene regulation

Strong

32

Cystitis or other urinary
tract infection

Chronic inflammation

Cell-cycle regulation, cell
death, gene regulation

Moderate

1

Urinary calculi

Chronic inflammation

Cell-cycle regulation, cell
death, gene regulation

Weak

1

Annu. Rev. Pathol. Mech. Dis. 2009.4:251-285. Downloaded from arjournals.annualreviews.org
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Occupation

Diet

Drugs and therapies
Phenacetin,
cyclophosphamide,
pelvic irradiation
Urologic pathologies

(Continued )
www.annualreviews.org • Bladder Cancer

253

as they are exposed to carcinogens in diesel exhaust (21). primarily as a result of better safety equipment (20). These dyes belong to a class of chemicals known as arylamines. Firefighters are exposed to both aromatic amines and polycyclic aromatic hydrocarbons. especially deletion of part or all of chromosome 17p (26). A number of other occupations with related exposures to aromatic amines have been associated with increased risk of UC. DRESDEN on 11/13/09. Downloaded from arjournals. 2009.4:251-285. they are more controversial for coffee consumption. Mech. nongenotoxic mechanisms such as peroxisome proliferation and hypomethylation of DNA may contribute to tumor development (23). Family history carcinogens that can form highly reactive species and DNA adducts (8). However. Although the data on tea consumption are largely negative for risk of UC. especially in some regions of Bangladesh. Although their genotoxicity is equivocal. the association of personal hair dye use and UC risk is relatively weak (10). Initial evidence indicates that workers who manufactured aniline dyes used for coloring fabrics were at increased risk (1). production of which has been dramatically reduced since the 1950s. Mutagenic compounds with chemical structures similar to aromatic amines were used in hair dyes in the early 1970s. Taiwan.L.ANRV368-PM04-11 Table 1 ARI 9 December 2008 15:4 (Continued ) Risk factor Mechanism of carcinogenesis Primary cellular process(es) altered Strength of association Reference(s) Ancestry and genetics Genetic predisposition Depends on the genetic alteration(s) Strong 33 NAT2 polymorphism Inefficient detoxification of aromatic amines Gene regulation Strong 35 NAT1 polymorphism Promotion of formation of DNA adducts of aromatic amines Gene regulation Inadequate 37 GSTM1 polymorphism Inefficient detoxification of carcinogens Gene regulation Weak 38 Annu. 18) and asphalt paving (19). and Chile. Pathol. Inactivation of the p53 protein has been suggested to be a plausible mechanism by which hair dyes alter normal cellular processes (9). although large .U.annualreviews. as is suggested by the decreasing trend in UC incidence among hairdressers in recent decades (11).org by WIB6149 . Increased risk is also observed in occupations that entail exposure to polycyclic aromatic hydrocarbons. such as aluminum smelting (17.S. These aniline dyes and aromatic amines form DNA adducts (12) and reduce the DNA-repair capacity of the cell (13). their risk of UC is lower than in previous decades. painting (15). It is possible that the risk is smaller with the newer formulations of hair dyes. including rubber manufacturing (14). thereby making cells more susceptible to DNA damage. High arsenic levels in drinking water. However. Rev.B. 254 Mitra · Cote leather processing. For personal use only. Studies have shown a marginally elevated relative risk of UC in coffee drinkers (27). Long-term consumption of water containing chlorine and chlorination by-products can increase the risk of UC (22). UC incidence has increased with industrialization. An increased risk has been reported among workers involved in dyestuff manufacturing involving aromatic amines. but no trends in relation to dose or duration of consumption have been established (24). Dis. are another major bladder carcinogen (24). Arsenic exposure has been associated with RASSF1A promoter methylation (25) and with gains and deletions of several chromosomes. The mechanisms by which polycyclic aromatic hydrocarbons cause cellular alterations are similar to those of aromatic amines. Defects in genes that can repair DNA damage can lead to further genetic deregulations and alterations in cellular homeostasis. Finally. and printing (16). which include 2-naphthylamine and aminobiphenyl. Argentina. Commercial truck drivers are also at higher risk.

CIS and invasive tumors show frequent alterations in the TP53 and RB genes and pathways (45). compared with 10% to 20% of invasive tumors (41–43) (Figure 3). such as a stone or a catheter. Dis.annualreviews. The NAT2 enzyme is polymorphic. and chronic infection with this parasite produces toxins. Homozygous deletion of the GSTM1 gene that encodes glutathione S-transferase M1. and in “slow” acetylators where its activity is reduced. UC risk is increased by approximately 50% to 100% in first-degree relatives of UC patients (33). In Egypt and parts of the Middle East. ANRV368-PM04-11 ARI 9 December 2008 15:4 quantities of saccharine do have a carcinogenic effect in rats (28). For personal use only. although Hartmann et al. However. Approximately 70% of low-grade Ta tumors harbor FGFR3 mutations. which can remodel the extracellular matrix (ECM) and promote tumor angiogenesis. A variant polyadenylation signal of the NAT1 gene is associated with increased enzyme activity (36) and can promote the formation of DNA-binding metabolites of aromatic amines within the urinary bladder. has been suggested to increase the risk of UC. an enzyme involved in detoxifying various carcino- gens. thereby exerting a genotoxic effect (31). and N-nitrosamines. inflammation. whereas nonsteroidal anti-inflammatory drugs may lower the risk (30). Heavy consumption of phenacetincontaining analgesics has been linked to an increased risk of UC.4:251-285. Acetyltransferases detoxify aromatic amines by N-acetylation and O-acetylation of their N-hydroxy derivatives. Low-grade papillary tumors usually have a constitutively active receptor tyrosine kinase–Ras pathway. www. Pelvic irradiation is also another risk factor. Cyclophosphamide chemotherapy also increases the risk (1) via the same carcinogenic mechanism as phenacetin (31). exhibiting activating mutations in the Harvey rat sarcoma viral oncogene homolog gene (HRAS ) and in the fibroblast growth factor receptor 3 (FGFR3) gene. 2009. although they can also activate DNA-binding metabolites such as aryldiamine benzidine (34). Human Nacetyltransferase (NAT) activity is encoded by two genes.L.annualreviews. although the evidence is not conclusive (38). When the occasional papillary tumor does transform to an invasive phenotype. (47) found chromosome-9 deletions in both dysplastic urothelium and CIS lesions.org • Bladder Cancer FGFR: fibroblast growth factor receptor Loss of heterozygosity: loss of an allele from a heterozygous cell locus.S. but it rarely invades the basement membrane or metastasizes.B. resulting in DNA damage (32).U. DRESDEN on 11/13/09. NONINVASIVE AND INVASIVE BLADDER CANCERS There are two forms of noninvasive bladder cancer. although these pathways may not always be mutually exclusive (40) (Figure 2). High-grade Ta tumors are often characterized by homozygous deletion of the p16INK4a gene (44). p16 alterations have also been identified in invasive tumors (48). NAT1 and NAT2. The genesis of Ta tumors follows a molecular pathway that is usually distinct from CIS and the invasive (T1–T4) cancers (39). In contrast. matrix metalloproteinases (MMPs). The papillary carcinoma (Ta) phenotype has a tendency to recur locally. and UC is an important consideration in patients with a radiated pelvis who present with hematuria (1). Loss of heterozygosity of chromosome 9q is usually more prevalent in low-grade Ta tumors (46). These are Schistosoma haematobium–endemic areas. vascular endothelial growth factor (VEGF). is also related to UC development (1). Downloaded from arjournals. However. can result in tumor-suppressorgene inactivation if the other allele is mutated MMP: matrix metalloproteinase VEGF: vascular endothelial growth factor ECM: extracellular matrix 255 . it is usually a result of the accumulation of additional alterations in molecules in the p53 pathway (45). Phenacetin has been shown to cause single-strand DNA breaks. the risk of UC increases (35). and thrombospondin1 (TSP-1). Alterations in cadherins. the flat carcinoma in situ (CIS) is a dangerous lesion with a high tendency for invasion and metastasis. Rev. the NAT1 genotype has not been associated with increased UC risk (37).org by WIB6149 . Chronic bladder inflammation secondary to urinary tract infection or to an indwelling foreign body. squamous cell carcinoma is the most common form of bladder cancer. the association between artificial sweeteners and UC in humans has largely been inconclusive (29). Mech. Pathol.Annu. are seen more commonly in the muscleinvasive (T2–T4) tumors (39).

L. high-grade. In addition to the differences in molecular alterations between noninvasive and invasive UC. HRAS.U. The thickness of the arrows is approximately proportionate to the relative frequency of occurrence.org by WIB6149 . HG. Loss of heterozygosity of 9q is more common in low-grade papillary carcinomas (Ta). and this is especially true in current smokers (as opposed to ex-smokers) (49). chromosomal alterations. and therapeutic management be256 Mitra · Cote tween these two clinical phenotypes (Figure 3). low-grade. protein of the Harvey rat sarcoma viral oncogene homolog gene. Rev. Although noninvasive tumors have constitutive activation of the Ras-MAPK (mitogen-activated protein kinase) pathway. Smokers have a much higher risk of developing invasive tumors than noninvasive tumors.4:251-285. Downloaded from arjournals. Pathol. clinical outcome. Invasive tumors . retinoblastoma protein. flat carcinoma in situ (CIS) and invasive lesions have alterations in p53 and other cell-cycle-regulatory molecules. DRESDEN on 11/13/09.B. there are also marked contrasts in epidemiology. extracellular matrix. Mech. respectively.ANRV368-PM04-11 ARI 9 December 2008 15:4 9Rb p16 p53 Rb CIS Annu. fibroblast growth factor receptor 3. Locations of molecules indicate characteristic alterations that pose a risk for progression of a particular phenotype. Dis. FGFR3. Abbreviations: ECM. 2009. p16 p53 ? Ta (HG ) T1 p21 T2a p16INK4a G) Ta (L T2b al rm ium No thel o ur 9qHRAS T3a Lamina propria T3b Epithelium T4a 3 FGFR3 Musculariss propria Perivesical fat Pros ostate Urethra ret ECM remodeling genes Figure 2 Composite model for urothelial tumorigenesis and progression. Noninvasive and invasive tumors are characterized by distinct molecular alterations.S. For personal use only. Rb. although deletions of chromosome 9 are also seen in progressive CIS.annualreviews. Locations of the arrow tails and heads correspond to the tumor stage(s) before and after alteration(s) of the denoted molecule(s). LG.

the risks of disease progression and death increase with invasion.L. This causes increased intranuclear accumulation of the protein. to identify organ-confined invasive UC patients with the greatest risk of progression (i. transurethral tumor resection and intravesical Bacille Calmette-Gu´erin are generally recommended in superficial (Ta– T1) tumors. in turn. Consequently. which. Alterations within many of these molecular pathways have been identified in UC.annualreviews. a significant discordance does exist. node-negative (T1–2bN0) UC (59–61). However. PROGNOSTIC IMPACT OF FUNCTIONAL ALTERATIONS IN BLADDER CANCER Tumorigenesis involves multiple alterations in several tightly controlled pathways that otherwise interact normally within a molecular circuitry to maintain cellular homeostasis (Figure 4). From a therapeutic standpoint. Although the risk of local recurrence is very high in Ta tumors. This led to the institution of the first international multicenter clinical trial in UC that targeted molecular lesions. Although most UCs exhibit loss of a single 17p allele. organ-confined. although conventional chemotherapy has limited benefits in UC patients. TP53 mutations result in an altered protein that is resistant to normal regulatory ubiquitin-mediated degradation. and gene regulation processes (Figure 4). are closely associated with the apoptotic. Located on chromosome 17p13. 55). and radical cystectomy is generally advocated in T1–T3 tumors (51). and they may also act as druggable targets (52). resulting in apoptosis (63). the TP53 tumor-suppressor gene encodes for p53. p53 inhibits cell-cycle progression at the G1 -S transition and mediates its control through the transcriptional activation of p21WAF1/CIP1 .org by WIB6149 .. Rev. Pathol. DRESDEN on 11/13/09. those tumors with a mutated TP53 and an altered protein phenotype exhibit the worst prognosis and those with a wild-type gene and an unaltered protein perform the best (Figure 5) (67). patients with p53-altered tumors) who would respond best to cisplatin-containing chemotherapy (64). also have more chromosomal aberrations than Ta tumors (50). evidence suggests that patients with locally advanced UC who harbor p53 alterations respond beneficially to adjuvant chemotherapy that contains DNAdamaging agents such as cisplatin (62). 2009. Downloaded from arjournals. it is their net effect on the deregulation of key cellular processes that establishes the tumor and controls its fate. Normally. Our studies examining p53 immunoreactivity with the corresponding TP53 mutations in primary UC suggest that although both nuclear accumulation and gene mutations are independent prognostic indicators. For personal use only.1. However.annualreviews. Mech. the central protein of the p53 pathway (53). it appears that www. The cell cycle is primarily controlled by the p53 and retinoblastoma (Rb) pathways.4:251-285. which can be detected by immunohistochemistry (58). it decreases with invasion (51). mutation in the remaining allele can inactivate TP53. More importantly. the short half-life of p53 (6–30 min) prevents its accumulation in the nucleus (57). The plausible explanation is that DNA damage to p53-altered urothelial cells might cause an uncoupling of the S and M phases of the cell cycle.S. 66). However.ANRV368-PM04-11 ARI 9 December 2008 15:4 Annu. Although p53 nuclear accumulation is correlated with TP53 mutations (65.e. Dis.B. Alterations in Cell-Cycle Regulation Alterations in the cell cycle are probably the most extensively investigated aspects of the molecular characterization of UC. and although cisplatin-based combination therapies show mixed to modest benefits in the adjuvant and neoadjuvant settings (45). alterations in key molecular markers are important predictors of outcome and therapeutic response (Table 2). loss of heterozygosity on chromosome 17 occurs during the later stages of UC and is usually associated with a more aggressive phenotype (56).org • Bladder Cancer 257 . We and others have shown that p53 nuclear immunoreactivity is predictive of outcome particularly for patients with invasive. signal transduction. However.U. leading to loss of its tumor-suppressor function (54. Furthermore.

annualreviews. Pathol.org by WIB6149 . For personal use only.U. Rev.ANRV368-PM04-11 ARI 9 December 2008 15:4 Superficial Invasive Noninvasive Relative risk of bladder cancer (compared to nonsmokers) b 7 6 5 4 3 2 1 0 Average frequency of alterations Annu. DRESDEN on 11/13/09. Downloaded from arjournals. 2009. Dis.S. a Ta 16 14 12 10 8 6 4 2 0 Genetic alterations (% cases) c d With respect to the muscularis propria Muscle-invasive T1 T2 T3 With respect to the basement membrane T4 Ex-smoker (<20 cigarettes per day) Ex-smoker (>20 cigarettes per day) Current smoker (<20 cigarettes per day) Current smoker (20-39 cigarettes per day) Current smoker (>40 cigarettes per day) Chromosomal loss Chromosomal gain Chromosomal amplification 80 70 60 50 HRAS-activating mutation FGFR3-activating mutation p53 alteration p21 alteration Rb alteration p16 alteration 40 30 20 10 0 Relative risk High Moderate Low Recurrence Progression Mortality Minimal None Mitra Recommended therapy e 258 Tumor stage · Cote Yes Extensive comorbid disease/ poor performance status Transurethral tumor resection Intravesical Bacille Calmette-Guérin Yes Yes Palliative (select T4aN0) Radical cystectomy .B.4:251-285. Mech.L.

which acts as a CDKI.org • Bladder Cancer 259 . ANRV368-PM04-11 ARI 9 December 2008 15:4 the site of TP53 mutation may also be an important prognostic factor. resulting in CDKI: cyclindependent kinase inhibitor Single nucleotide polymorphism (SNP): genomic DNA sequence variation due to differences in a single nucleotide. A study showed that homozygous p16INK4a deletions in superficial UC had a higher recurrence rate. Mech. transurethral resection may also be employed in patients with muscle-invasive tumors with extensive comorbid disease or poor performance status (orange bar). and it can provide an enhanced prognostic value when coupled with TP53 mutation status (71). Loss of p21 expression is a potential mechanism by which p53 alterations influence tumor progression. Active. Harvey rat sarcoma viral oncogene homolog gene. Encoded on chromosome 12q14.org). www. a cyclindependent kinase inhibitor (CDKI) that is transcriptionally regulated by p53.L. and amplifications. Dis. encodes the Rb protein. However. Rev. The translated protein then mediates the proteasomal degradation of p53. (b) Invasive tumors also have a higher frequency of chromosomal losses. present in >1% of the population Supplemental Material ←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 3 Differences between noninvasive and invasive bladder tumors. has been reported to predict younger age at disease onset and poorer survival. (d ) Invasive tumors have a lower chance for recurrence. which interacts with multiple regulatory proteins involved in the G1 -S transition. and its frequency increases with increasing tumor stage and grade (70). The other splice variant. (73) noted that p14ARF inactivation usually occurs by homozygous deletion. a single nucleotide polymorphism (SNP) in the MDM2 promoter region. the p21WAF1/CIP1 gene encodes for p21. other groups have observed higher methylation rates for p14ARF than p16INK4a (74). fibroblast growth factor receptor 3 gene. Pathol.B. noninvasive tumors refer to those that do not invade the basement membrane (Ta). Increased p53 levels transactivate the MDM2 promoter. and palliative radical cystectomy may be performed in select T4a patients without metastatic lymph nodes who are responsive to chemotherapy ( pink bar). but it concluded that only those deletions affecting both p16 and p14.annualreviews.annualreviews. For personal use only. Superficial bladder tumors are lesions that do not invade the muscularis propria (Ta. Upon phosphorylation of the protein (pRb) by cyclin-dependent kinases (CDKs). correlated with the worst prognosis (44).Annu. 2009. (c) Although mutations in HRAS and FGFR3 decrease with invasion. follow the Supplemental Material link from the Annual Reviews home page at http://www. HRAS. encodes for p16.4:251-285. Located on chromosome 6p21. causing its upregulation. which deregulate both Rb and p53 pathways. the Mdm2 protein is involved in an autoregulatory feedback loop with p53. Abbreviations: FGFR3. located on chromosome 13q14.S. gains. Berggren et al. however. (e) Transurethral tumor resection and intravesical Bacille Calmette-Gu´erin instillation are generally recommended for superficial tumors (Ta–T1). DRESDEN on 11/13/09.U. The retinoblastoma gene (RB). the opposite is true for p53. Rb. it forms the biochemical link between the Rb and p53 pathways (72). retinoblastoma protein. dephosphorylated Rb binds and sequesters the transcription factor E2F. p16INK4a . E2F is released.3-q15. Rb. SNP309. We have shown that loss of p21 expression is an independent predictor of UC progression and that the maintenance of expression appears to abrogate the deleterious effects of altered p53 (68). although p16INK4a is the hotspot for hypermethylation in UC. and p16 alterations. However.annualreviews. p14ARF may be inactivated by homozygous deletion (73) or by varying degrees of methylation of the promoter region (see Sidebar and Supplemental Table 1. Also. which is situated on chromosome 9p21. although it can also be regulated in a p53-independent manner (Figure 4). MDM2 is transcriptionally inhibited by p14. The protein is encoded by p14ARF . and radical cystectomy is advocated for the invasive (T1–T3) tumors. (a) The relative risk of developing invasive bladder cancer is higher in smokers than in nonsmokers. but they are more prone to progression and increased risk of death. p21. The resultant lowered p53 levels then reduce the levels of Mdm2. Because p14ARF is induced by the transcription factor E2F. thus controlling its activity (Figure 4) (69). MDM2 amplification has been observed in UC. T1). Downloaded from arjournals.org by WIB6149 . one of the two splice variant transcripts derived from the single CDKN2A locus.

2009.S. which results from loss of p16 expression and/or cyclin D1 overexpression Grb2 Sos Ras VEGFR2 PIP3 PI3K JAK Cytoplasm RASSF1a PKC Raf PLC PTEN E-cadherin PDK1 MEK Akt ERK β-catenin DAPK Cytokine receptor STAT1 STAT3 STAT1 STAT3 ERK Nucleus MSK1 RSK Bad CDKN2A Cyclin E p27 CDK2 Rb E2F p21 p53 Mdm2 p14 E2F pRb c-Fos Caspase-6 Apaf-1 Caspase-9 Caspase-7 Caspase-10 Caspase-8 Caspase-3 FADD ASK1 MKK7 JNK TRADD FADD Gene expression changes Apoptosis Bid TNFR Cyclin D1 CDK4 Bax Cytochrome c Fas p16 c-Myc Cdc25a Bcl-2 Bcl-X L Mitochondrion Annu. Downloaded from arjournals. These tumors with the highest Rb expression levels demonstrate constitutively hyperphosphorylated Rb. results from our group indicate FGFR3 ANRV368-PM04-11 c--Jun c-Jun c-Ju c-J Jun HIF cIAP TRAF2 NIK IKK IκB NF-κB B NF-κB HIF VEGF TP MMP-2 MMP-9 Hyp ypoxia Tumor blood vessell 260 Mitra · Cote uPA plasmiin n bFGF bFGF aFGF SF α6β4 integrin TSP-1 IL-8 ECM . Inactivating RB mutations that result in loss of protein expression have been observed across all tumor stages and grades of UC (75). Mech. Rev.org by WIB6149 . the transcription of genes required for DNA synthesis. Pathol.annualreviews.U.ARI 9 December 2008 15:4 EGFR ErbB-2 VEGFR2 EGFR Src that a significant proportion of Rb-expressing tumors show clinical consequences of loss of Rb function (76). DRESDEN on 11/13/09.L. Although it was originally believed that the presence of Rb nuclear immunoreactivity indicated the presence of an intact functional gene and that the loss of protein expression indicated RB mutations. Patients with such tumors have high Rb expression but have a clinical outcome similar to that of patients with no Rb expression. For personal use only.B. Dis.4:251-285.

A similar scenario is observed with methylation reports on p14ARF and p16INK4a . PIP3 . The specific complexes that phosphorylate Rb are cyclin D1/CDK4/6 and cyclin E/CDK2. c-Jun N-terminal kinase. and p27. PLC. Studies investigating the combined effect of p53 and Rb pathway alterations on UC prognosis have also shown promising results. aberrant hypermethylation of CpG islands in the promoter regions of tumorsuppressor genes is a frequent. ERK. has shown more consistent methylation levels across studies and holds promise as a reliable prognostic marker. PTEN. JAK. Rb phosphorylation is facilitated by the cyclin/CDK complexes. PDK. activator of S phase kinase 1.B. phosphatidylinositol (3. thrombospondin. pRb. extracellular matrix. ECM. 2009. tumor necrosis factor (TNF) receptor–associated death domain. This leads to gene-expression changes that are controlled by key transcription factors ( yellow). Janus kinase. yet potentially reversible mechanism of transcriptional suppression in UC (Supplemental Table 1. Further. phosphorylated retinoblastoma protein.org • Bladder Cancer 261 . TSP. Rev. vascular endothelial growth factor receptor 2. The tumor cell also interacts with factors controlling angiogenesis ( green) and invasion (orange). extracellular signal–regulated kinase.L. matrix metalloproteinase. scatter factor. Other studies have conducted similar analyses using various marker combinations of p53. basic fibroblast growth factor. TNF receptor–associated factor. Our studies examining the combined effects of p53. p16. However.annualreviews. acidic fibroblast growth factor. follow the Supplemental Material link from the Annual Reviews home page at http://www. p21. www. A complex network of molecular signaling is involved in malignant transformation and tumor progression. Downloaded from arjournals. TRAF. p16. and induction of chromosomal instability by DNA hypomethylation. Mech. SF.4. when this occurs in the coding regions of genes. the frequency of CDK4 amplification is significantly linked to higher grade and invasive potential (70).and intercellular circuitry contributing to bladder tumorigenesis. Abbreviations: aFGF.U. and Mdm2 to generate prognostic panels (81–85) and have demonstrated a synergism between these markers in bladder tumorigenesis. protein kinase C. VEGFR2. progression. ribosomal S6 kinase.5)–trisphosphate. Fas-associated protein with death domain. Rb. FADD. Dis. MMP. Although a rare event in UC. DAPK. Low p27 levels have been associated with shortened disease-free and overall survival in UC (78). DRESDEN on 11/13/09. However. p21. thereby inhibiting signaling via the Ras-MAPK pathway. phosphatase and tensin homolog deleted on chromosome 10.org).org by WIB6149 . ROLE OF METHYLATION DNA methylation exerts its effects on the human genome through the mutational burden of 5-methylcytosine. TRADD. RASSF1A. ANRV368-PM04-11 ARI 9 December 2008 15:4 (77). The covalent addition of a methyl group to cytosine at CpG palindromes by DNA methyltransferase results in the formation of 5-methylcytosine. which encodes for the protein that prevents ERK (extracellular signal–regulated kinase) translocation from the cytoplasm to the nucleus.4:251-285.S. PI3K. mitogen.annualreviews. mitogen-activated protein kinase (MAPK)/ERK kinase. JNK.annualreviews. Negative regulation of the CDKs is achieved by CDKIs such as p21. ASK1. Pathol. Alterations in Cell Death Pathways Supplemental Material The series of cell death events that occur throughout normal development and in ←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Figure 4 Intra. it can result in a nonfunctional protein. phosphatidylinositol 3–kinase.Annu. This provides the biologic basis for constitutive Rb inactivation in the presence of an intact gene through Rb hyperphosphorylation. death-associated protein kinase. phospholipase C. 3 -phosphoinositide-dependent kinase. PKC. urokinase-type plasminogen activator. This is notable in the case of DAPK (death-associated protein kinase). This increases the probability of C → T transition mutations by a deamination reaction. and outcome prediction. RSK. HIF. Early studies on combined Rb and p53 expression revealed that abnormal expression of either or both proteins was significantly associated with an increased risk of progression in T1 tumors (79). which encodes for a protein that can inhibit Ras function. uPA. and Rb alterations have shown that an incremental increase in the number of altered markers is associated with poorer recurrence-free and overall survival (80). MEK. For personal use only. heritable. Mitogenic signals from growth receptors ( gray) on the cell surface are conducted along signal transduction pathways (molecules in black) to affect cell-cycle regulation (molecules in purple) and apoptosis (molecules in blue). which act as tumor suppressors. variations in the prevalence of methylation levels of genes reported by various studies in UC hinder their applicability as potential prognostic indicators. bFGF. MSK1. hypoxia-inducible factor. epigenetic effects of promoter methylation.and stress-activated kinase 1.

DRESDEN on 11/13/09.4:251-285. transmits angiogenic signals Ras-MAPK.U.S. 2009. decreased overall survival Caspase-3b Promotes apoptosis Common apoptosis effector Increased recurrence FGFR3e Receptor for fibroblast growth factor. amenable to cisplatin chemotherapy p21b Cyclin-dependent kinase inhibitor p53 Increased recurrence. promotes apoptosis Extrinsic apoptotic Decreased cause-specific survival Bcl-2c Inhibits caspase activation Intrinsic apoptotic Decreased survival. Dis. c-Fos.ANRV368-PM04-11 Table 2 ARI 9 December 2008 15:4 Molecules and processes contributing to urothelial turmorigenesis Marker/ expression in urothelial carcinoma Molecular pathway(s) involved Normal function Prognostic impact Annu. PI3K-Akt Increased progression. NF-κB. decreased survival Rbd Sequesters E2F.org by WIB6149 . transmits growth signals Ras-MAPK. nodal metastasis Cell death Cell growth Signal transduction HRASc Activates Raf and PI3K Ras-MAPK Increased in nonprogressing Ta tumors PKCf Activates Raf. For personal use only. involved in the G1 -S transition Rb Increased with tumor stage and grade p27b Cyclin-dependent kinase inhibitor Rb Decreased survival Fasb Activation signals formation of death-inducing signaling complex. increases Bcl-2. antagonizes PI3K signaling PI3K-Akt Decreased with tumor stage and grade Gene regulation STAT3c Regulates gene expression.B. inhibits cell-cycle progression Rb Increased recurrence. decreased survival ErbB-2c Receptor for epidermal growth factor. poor prognosis with adjuvant therapy Baxb Releases cytochrome c from mitochondria. inhibits Bad PLC/PKC Increased recurrence PTENb Dephosphorylates PIP3 .L. Cell-cycle regulation p53a Inhibits G1 -S progression p53 Increased recurrence. Mech. transmits growth signals Ras-MAPK.annualreviews. Bcl-XL expression JAK-STAT Increased recurrence. PI3K-Akt Decreased survival VEGFR2c Receptor for vascular endothelial growth factor. decreased survival. decreased survival NF-κBg Regulates gene expression NF-κB Increased recurrence with homozygous insertion c-Fosc Regulates gene expression MAPK Increased with tumor grade c-Junc Regulates gene expression MAPK Increased recurrence. promotes apoptosis Intrinsic apoptotic Poor prognosis. decreased survival Mdm2c Mediates the proteasomal degradation of p53 p53 Increased with tumor stage and grade p14b Inhibits MDM2 p53 Decreased survival p16b Cyclin-dependent kinase inhibitor Rb Increased recurrence. Downloaded from arjournals. decreased survival 262 Mitra · (Continued ) Cote . PI3K-Akt Increased with disease stage. transmits growth signals Ras-MAPK Increased recurrence EGFRc Receptor for epidermal growth factor. invasion. decreased survival CDK4c Complexes with cyclin D1. Pathol. Rev.

bFGF. fibroblast growth factor receptor 3. epidermal growth factor receptor. The extrinsic pathway involves activation of death receptors on the cell surface.L. decreased survival α6β4 integrinh Links collagen VII to the actin cytoskeleton. hypoxia-inducible factor. i Uncertain. NF-κB. vascular endothelial growth factor. Rev. induces MMP uPAc Degrades extracellular matrix bFGFc Growth factor stimulating angiogenesis Ras-MAPK Increased risk of local recurrence aFGFc Growth factor stimulating angiogenesis Ras-MAPK Increased with increasing stage SFc Growth factor stimulating angiogenesis TSP-1b Inhibits angiogenesis p53 Increased recurrence. HIF. urokinase-type plasminogen activator.org • Bladder Cancer 263 . Downloaded from arjournals. uPA. phosphatidylinositol trisphosphate. c Overexpressed. For personal use only. acidic fibroblast growth factor. phosphatase and tensin homolog deleted on chromosome 10. Both pathways activate caspases that cleave cellular substrates and lead to the characteristic biochemical www. decreased survival (?) Increased recurrence. signal transducer and activator of transcription.org by WIB6149 . VEGFR2. whereas the intrinsic pathway is mediated by mitochondria (Figure 4). e Overactivated.U. cyclin-dependent kinase. TSP-1. TIMP-2. d Lost/hyperphosphorylated. MAPK. h Lost/overexpressed. mitogen-activated protein kinase. PLC. decreased survival Increased recurrence Increased progression. Dis. decreased survival MMP-9c Degrades extracellular matrix Increased with tumor stage and grade TIMP-2i Antagonizes MMP function Increased recurrence. g Polymorphic insertion/deletion in promoter region.annualreviews.4:251-285. It is quantified by the apoptotic index. Rb. SF. decreased survival E-cadherinb Mediates intercellular adhesion Cadherin Increased recurrence and progression. Mech. PI3K-Akt Increased recurrence and progression. Tumor angiogenesis HIFc Transcribes genes responsible for angiogenesis VEGFc Promotes angiogenesis through nitric oxide synthase TPc Promotes VEGF and interleukin-8 secretion. decreased survival Ras-MAPK. DRESDEN on 11/13/09. thrombospondin-1. VEGF receptor 2. protein kinase C. decreased survival Increased compared to normal controls Invasion a Altered. MMP.annualreviews. STAT. scatter factor. matrix metalloproteinase. tissue inhibitor of metalloproteinase 2. the ratio of apoptotic cells to the total number of tumor cells. Apoptosis can be initiated by two alternative pathways. VEGF.ANRV368-PM04-11 Table 2 ARI 9 December 2008 15:4 (Continued ) Marker/ expression in urothelial carcinoma Molecular pathway(s) involved Normal function Prognostic impact Annu. PTEN. Pathol. PIP3 . retinoblastoma protein. b response to a variety of initiation stimuli is referred to as apoptosis.B. thymidine phosphorylase. protein of the Harvey rat sarcoma viral oncogene homolog gene. Abbreviations: aFGF. PKC. EGFR. phosphatidylinositol 3-kinase. 2009. phospholipase C. CDK. f Overexpressed in membrane. PI3K. transduces regulatory signals Cytoskeletal signaling Decreased survival MMP-2c Degrades extracellular matrix Increased recurrence. decreased survival β-cateninb Links cadherins to the actin cytoskeleton Wnt/β-catenin Increased progression. nuclear factor–kappa B.S. Underexpressed/lost. and has been correlated to tumor progression as well as to recurrence-free and overall survival of patients with superficial tumors (86). JAK. basic fibroblast growth factor. Janus kinase. FGFR3. HRAS. TP.

altered.001). and antisense downregulation of this protein in bladder cancer cell lines sensitizes them to cytotoxic agents (100). Bad inhibits Bcl-XL and possibly Bcl-2. but there is little evidence to suggest that alterations in this molecule contribute to bladder tumorigenesis (101). which can activate the proapoptotic protein Bax. Abbreviations: alt.001 0. Cellular stress causes rapid opening and closing of the mitochondrial megapores. Dis. it includes antiapoptotic members such as Bcl-2 and Bcl-XL as well as proapoptotic members such as Bax.25 Mut gene. it regulates the formation of “megapores” that control ionic flux and maintain potential across the mitochondrial membrane (53). Alternatively. -6. in vitro tumor-specific caspase8 expression has been shown to induce apoptosis in UC cell lines (91). encodes the antiapoptotic Bcl-2 protein. and morphological changes. Maluf et al. Reproduced with permission from Reference 67. p53. and Bcl-2 where normal expression of all markers was significantly correlated with the best survival probability and where aberrations in all three markers corresponded to the worst survival probability. ANRV368-PM04-11 ARI 9 December 2008 15:4 1. which inhibits caspase activation. UC have been shown to acquire mechanisms to escape Fas-mediated apoptosis in the course of malignant transformation (87). Bcl-2 immunoreactivity has been associated with decreased tumorfree survival in T1G3 tumors (96) and can be a good indicator of mortality in superficial UC in combination with p53 (97).00 Wt gene. whereas those with a mutated TP53 gene and positive p53 immunoreactivity (altered protein) perform the worst. Interaction of death receptors with their respective ligands allows the formation of a death-inducing signaling complex.U. Downloaded from arjournals.4:251-285.18)bearing human follicular B cell lymphomas (92). Decreased Fas immunoreactivity in UC has been associated with a higher stage and grade. Pathol.org by WIB6149 . The BCL2 gene. wild-type. mutated. Initiator caspases may directly activate “effector” caspase-3.Estimated probability of not recurring Annu. identified at the chromosomal breakpoint of t(14. which function as “initiator” caspases. American Society of Clinical Oncology.B. which results in apoptosis. Bcl-2 can also identify patients with advanced UC undergoing radiotherapy who may benefit from neoadjuvant chemotherapy (95). causing release of stored calcium and cytochrome c and thereby activating effector caspases and leading to . Patients with bladder tumors with a wild-type TP53 gene and negative p53 immunoreactivity have the best prognosis. (98) established a prognostic index using Mdm-2.L. As expected. This alters the mitochondrial membrane potential. The Bcl-2 family of proteins plays a crucial role in the intrinsic apoptotic pathway. which includes the FADD (Fas-associated death domain) protein.S. 264 Mitra · Cote they may activate Bid. and Bad (Bcl-XL /Bcl-2-associated death promoter).00 0 5 10 15 20 Years since cystectomy Figure 5 Prognostic relationship between TP53 mutations and p53 protein status. wt. Members of the TNFR (tumor necrosis factor receptor) superfamily include death receptors such as Fas. Tumors in patients with either a mutated gene or an altered protein have intermediate probabilities of not recurring (logrank P < 0. which direct Bax to the site. alt protein (n=26) P < 0. Localized on the outer mitochondrial membrane. alt protein (n=28) 0. and -7. Copyright 2008. For personal use only. A possible mechanism could be due to the presence of circulating soluble Fas that antagonizes cellsurface Fas function (88). Bid. mut.annualreviews.50 Wt gene. Bcl-XL interacts and works with Bcl-2 in the progression of low-stage UC (99).75 Mut gene. as well as with poorer prognosis (90). Rev. Mech. wt protein (n=11) 0. The complex recruits caspase-8 and -10. Patients with aberrant expression of either one or two markers had an intermediate probability of survival. DRESDEN on 11/13/09. wt protein (n=85) 0. Bcl-2 overexpression correlates with poor prognosis in UC patients treated with radiotherapy (93) or synchronous chemoradiotherapy (94). 2009. a finding that has been corroborated in the urine of superficial UC patients (89).

Downloaded from arjournals.L. bind to and inhibit caspases and may also promote their ubiquitin-mediated degradation. 2009. 108).Annu. ANRV368-PM04-11 ARI 9 December 2008 15:4 apoptosis (53). Among the best-studied receptors in this family are EGFR (ErbB-1) and ErbB-2 (Her2/neu). Approximately 82% of grade 1 tumors and Ta tumors have mutations in either a Ras gene or FGFR3.S. Bax is an independent predictor of a more favorable prognosis in invasive UC (97. All VEGF family members stimulate cellular responses by binding to VEGF receptors (VEGFRs). 103). DRESDEN on 11/13/09. cIAP-2 has been identified as an important apoptotic regulator of UC cells in vitro. Deregulation in Cell Growth Signaling Several peptide growth factors and their associated tyrosine kinase receptors are responsible for modulating growth signals from external cues and transmitting them via signal transduction pathways into the nuclei of urothelial cells. MAPK: mitogenactivated protein kinase Alterations in Signal Transduction A variety of pathways are involved in transducing signals from cell-surface receptors to www. the combined expression profile of EGFR and ErbB-2 has been suggested to be a better predictor of outcome than each individual marker alone (114). This leads to the activation of the downstream effector caspases that drive apoptosis. increased ErbB-2 expression has been associated with worse disease-specific survival (108. Similarly. 112. Mutations in the FGFR3 and Ras genes are mutually exclusive (106). The epidermal growth factor receptor (EGFR) family consists of four closely related receptors that homo. and its overexpression may make tumors less susceptible to apoptosis-inducing therapies (105). Rev. The inhibitor of apoptosis (IAP) proteins.U. Increased EGFR expression has been associated with increased probability of progression and death (109–111).org by WIB6149 . thereby leading to uncontrolled cellular proliferation and tumor formation. 113). 102.org • Bladder Cancer 265 . Activating mutations of FGFR3 are the most extensively studied alterations in this receptor family.4:251-285. and this gene is strongly associated with the genesis of lowgrade papillary tumors (41–43). regulating cell-cycle progression. The FGFR family consists of four active members (FGFRs 1–4) of high-affinity cell-surface receptors. Unlike FGFR3. although this finding was not supported by another study (115). Dis. Pathol.or heterodimerize after ligand activation and transmit signals via the Ras-MAPK or phosphatidylinositol 3–kinase (PI3K)-Akt signal transduction pathways. Bax expression is controlled by p53 and JNK (c-Jun N-terminal kinase). Decreased caspase-3 expression has been associated with a higher probability of disease recurrence in cystectomy patients (104).annualreviews. Our studies have also shown that VEGFR2 may be an important determinant for prediction of nodal metastasis in UC patients (117). VEGFR2 (KDR/Flk-1) mediates most of the known cellular responses to VEGF. and other processes crucial to cancer progression (Figure 4). which probably reflects activation of the same pathway by either event. VEGFR2 expression has been correlated with increasing disease stage and tumor invasion into the muscle (116). One of the predicted effects of FGFR3 mutation is activation of the Ras–mitogen-activated protein kinase (MAPK) pathway (Figure 4). For personal use only. suggesting that activation of the MAPK pathway may be an obligate event in most of these cases. thereby activating it (53). such as cIAP. As mentioned above.annualreviews. forming the apoptosome that in turn activates procaspase-9 to active caspase9. these receptors are also overexpressed in invasive tumors (107. mitogenic signaling. This complex then binds to ATP. In the cytoplasm.B. Interestingly. Mech. Aberrations in these growth factor receptors and/or the signals transmitted by them can result in an abnormal increase in the rate of transduction of growth signals. VEGF is an important signaling protein involved in both vasculogenesis (formation of the embryonic circulatory system) and angiogenesis (growth of blood vessels from preexisting vasculature). cytochrome c binds to Apaf1. approximately 70% of low-grade Ta tumors harbor FGFR3 mutations. however.

PTEN can suppress growth and restore chemosensitivity in UC cell lines (128). which can dephosphorylate PIP3 and thereby antagonize PI3K signaling. Following JAK activation. a key ligand for the corresponding cytokine receptor. an antioxidant polyphenol found in . ANRV368-PM04-11 266 Mitra · Cote and that the levels of isozymes α. Activating Ras mutations are found in approximately 13% of Ta tumors and are not as common as FGFR3 mutations in this tumor stage (106). Akt is thus a key regulator of cell proliferation and survival and is often activated in UC (130). the PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor-suppressor gene encodes for PTEN. thereby controlling the cell cycle. The JAK family constitutes a distinct group of tyrosine kinases that is activated by cytokine and growth receptors and mediates multiple signaling pathways in normal cells. the most important signaling pathways identified to date include.annualreviews. a molecule upstream in the Ras-MAPK pathway (Figure 4). PI3K phosphorylates phosphoinositol lipids generating phosphatidylinositol trisphosphate (PIP3 ). presumably increase JAK signaling and are an independent predictor of recurrence and survival in UC patients (126). Studies have reported that the expressions of PKC isozymes β and δ decrease with increasing UC grade Annu. DRESDEN on 11/13/09. differentiation. and the nuclear factor–kappa B (NF-κB) pathway. including Mdm2. Downloaded from arjournals. To date. epigallocatechin gallate. phospholipiddependent enzyme. the Janus kinase ( JAK)–signal transducer and activator of transcription (STAT) pathway. c-Myc regulates cyclin expression and inhibits the activity of CDKIs. however. and apoptosis. compared with those that progress to an invasive phenotype (119). Most low-grade papillary tumors show constitutive activation of the Ras-MAPK pathway. Interestingly. subsequently leading to PKC activation (122). In addition to regulating transcription factors such as c-Fos and NF-κB. and ζ show the opposite pattern (123. and patients with superficial UC with a greater membrane/cytosol PKCα ratio have a higher risk of recurrence after chemotherapy (125). HRAS mutations have been observed in exfoliated cells in the urine of patients with low-grade bladder tumors (118).ARI 9 December 2008 15:4 transcription factors in the nuclei. ε. In UC. constitutive Ras-MAPK pathway activation does represent a dominant alteration in noninvasive tumors. The binding of a ligand to a tyrosine kinase receptor activates PLC and diacylglycerol. Akt activates several proteins in the cell-cycle-regulation process. while inhibiting Bad and Raf activity (Figure 4).S. Use of a PI3K inhibitor demonstrated increased radiosensitivity in nude mice bearing bladder tumor xenografts (127). PIP3 recruits PDK1 and Akt to the plasma membrane.L. p21. Mech. the Ras-MAPK pathway. generally through activating FGFR3 mutations (45). The ratio of PKCα expression in the membrane to that in cytosol has been reported to be greater in UC tissues and higher-grade tumors than in normal urothelium. Deregulations in these pathways can alter signal conduction. PKC can inhibit Bad activity and promote Raf.org by WIB6149 .4:251-285. Increased preoperative plasma levels of interleukin-6. Transduction of mitogenic signals along the pathway induces MYC. Recent studies from our group show that HRAS is significantly overexpressed in nonprogressing Ta tumors. In addition. is involved in signal transduction associated with cell proliferation. 121). the PI3K-Akt pathway. the phospholipase C (PLC)–protein kinase C (PKC) signaling cascade. Located on chromosome 10q23. PKC. 2009. In turn. Nevertheless. including PI3Ks. and expression of this protein is repressed with increasing UC stage and grade (129). thereby leading to abnormal regulation of genes. For personal use only. 124). a gene that encodes the transcription factor c-Myc (Figure 4) (45). JAKs mediate the recruitment of other signaling molecules. the best-characterized molecular events are tyrosine phosphorylation and activation of STATs. and p27. Once activated and localized to the membrane. Pathol.U. Dis. but may not be limited to. Rev.B. Certain PI3Ks can also be activated by receptor tyrosine kinase signaling or by Ras (Figure 4). a ubiquitous. cMyc has not proved to be a good prognostic indicator for UC (120. PDK1 then phosphorylates and activates Akt.

cytokines. Growth factors. and other signals can activate and translocate NF-κB into the nucleus by activating IκB kinase proteins that phosphorylate and consequently degrade IκB. form the AP-1 (activating protein 1) transcription factor complex (138). A study examining a functional insertion/ deletion polymorphism in the promoter region of NFKB1 showed that superficial UC patients with the homozygous deletion had a higher risk of recurrence than those with the homozygous insertion (137).S. c-Fos and c-Jun are strong transactivators that control basal and inducible transcription of several genes involved in proliferation. The NF-κB protein is an important transcription factor that plays a role in cellular gene regulation (discussed below). Bacille Calmette-Gu´erin–induced interleukin6 expression by UC occurs as an immediateearly gene pathway that requires NF-κB (136). (133) have shown that STAT1 can reduce the expression of Bcl-2 and Bcl-XL and that STAT3 has the opposite effect. We have shown that MVD is significantly associated with disease-free and overall survival in UC (141). Although the mechanism underlying regulation of the final target genes is not entirely clear.U. TNF. 2009. which results in modulation of the Bcl-2 protein family and enhances apoptosis (131). IκB sequesters NF-κB in the cytoplasm of most resting cells. autoimmune response. The hypoxia-inducible factors (HIF-1 and HIF-2) are heterodimeric transcription factors that are regulated by oxygen concentrations and that bind to DNA-upregulating neighboring genes (53).annualreviews. The JAK-STAT pathway results in the activation of STATs. Pathol. cell proliferation.4:251-285. For personal use only. Downloaded from arjournals. and apoptosis by regulating the expression of genes involved in these processes. Microvessel density (MVD): mean number of blood vessels over a number of randomly selected areas or in the densest areas of neovascularization (known as hot spots) Tumor Angiogenesis Angiogenesis involves production of factors by tumor cells that interact with stromal elements to recruit endothelial cells to the site of malignancy and establish a vascular supply. ANRV368-PM04-11 ARI 9 December 2008 15:4 green tea. which can provide the required nutrients for the rapid clonal expansion of the cancer cells. Angiogenesis is measured histologically by microvessel density (MVD) estimations. c-Fos expression has been correlated with increasing tumor grade (139). in combination with other related proteins.org • Bladder Cancer 267 . can predict increased risk of recurrence and decreased survival in UC patients (135). Although a comprehensive discussion of all the genes regulated by important transcription factors is beyond the scope of this review. in combination with other markers.Annu. whereas c-Jun expression has been correlated with increasing tumor stage in UC (140).B.org by WIB6149 . HIF-1α overexpression has been www. several other transcription factors regulate the expression of key genes in urothelial cells. NF-κB is another important transcription factor that plays an important role in in- flammation. DRESDEN on 11/13/09. Mech. 134). and deregulations in growth signals and signal transduction affect the functions of key transcription factors that act in the nucleus. Rev. apoptosis.annualreviews. Although hypoxia itself does not upregulate the transcription of the protein. The NF-κB pathway controls the activity of the transcription factor by its tightly regulated interaction with inhibitory IκB proteins (132). c-Fos and c-Jun are a pair of transcription factors that. Apart from E2F and cMyc (discussed above). it inhibits the oxygen-dependent degradation of the subunits. differentiation. Recent reports from our group indicate that increased STAT3 expression. which control the transcription of several important genes. Dis. has been shown to inhibit PI3K-Akt activation in bladder cancer cell lines. certain key factors are especially important in controlling the cellular processes and have major implications in urothelial tumorigenesis. Alterations in Gene Regulation Changes in cellular homeostasis are ultimately effected at the gene level. Stephanou et al.L. and transformation. including those that encode for the proapoptotic proteins Bcl2 and Bcl-XL (Figure 4) (133. Our recent studies also indicate that increased JUN expression is associated with poorer recurrence-free and overall survival in UC (135).

we do mention some of the key molecules involved. Recent evidence also suggests that patients who harbor two SNPs. Ubiquitous in all tissues. 2009. E-cadherin is the prototypic member of the classical cadherin family. urinary SF levels are significantly elevated in UC patients compared with other control cohorts (158). Dis. HIF-1α has also been shown to be significantly correlated with recurrence and survival in superficial UC (144). VEGF overexpression in superficial UC is associated with early recurrence and progression to a more invasive phenotype (146). For personal use only. facilitating endothelial cell migration and invasion. Additionally. Mech. and the corresponding protein levels in invasive tumors are 8-fold higher than in superficial tumors and 15-fold higher than in normal bladder tissue (150). and poor disease-free survival (147).annualreviews. and SF downstream. aFGF. uPA generates plasmin that stimulates bFGF. In addition to its role in cell-cycle regulation. as well as with shorter . We have shown that tumors with p53 alterations are associated with low TSP-1 expression and that these tumors demonstrate higher MVD (160). vascular invasion. Although an in-depth analysis of the pathways involved is beyond the scope of this review and has been covered elsewhere (161). Increased TP nuclear reactivity has been associated with a higher risk of recurrence in superficial UC (151. Pathol.B. Our studies have shown an association between p53 status and the degree of angiogenesis as measured by MVD. CIS. Experimental evidence also suggests that interleukin-8 is mitogenic and chemotactic for endothelial cells and that it enhances angiogenic activity and UC cell line invasion (153). Also. High serum VEGF levels have also been associated with high UC stage and grade.L. VEGF induces the formation of urokinase-type plasminogen activator (uPA). The MMPs activate basic and acidic fibroblast growth factors (bFGF and aFGF. which in turn restimulate the MMPs to bring about endothelial cell migration (Figure 4) (53). Urinary aFGF levels in invasive UC patients also show a strong correlation with disease stage (157). which degrades ECM.S. 152). this process contributes toward the invasion of tumor cells into the vasculature and lymphatics. VEGF in turn stimulates nitric oxide synthase. cadherins are prime mediators of intercellular adhesion. respectively). especially in conjunction with altered p53 expression (142. HIF induces VEGF transcription downstream. 143). MVD provided additional prognostic information in patients with p53altered tumors (159). E-cadherin’s cytoplasmic domain is linked to the actin cytoskeleton through critical interactions with catenins. Decreased E-cadherin expression has been significantly correlated with increased risk of tumor recurrence and progression.4:251-285. MMPs also stimulate scatter factor (SF).U. They are localized to adherens junctions and bind to their counterparts on adjoining cells as homodimers. Underexpression of TSP-1 is associated with decreased probabilities of recurrence-free and overall survival in UC. Preoperative plasma uPA levels are sig- Annu. DRESDEN on 11/13/09. In UC. which stimulates nitric oxide formation and tumor vascularization. ANRV368-PM04-11 268 Mitra · Cote nificantly associated with disease progression and death from UC (154). metastases. which stimulates angiogenesis. in the HIF-1α gene have significantly worse diseasefree and disease-specific survival than those without a variant allele (145).org by WIB6149 . Increase in Invasive Potential The process of invasion is a key feature of malignant growths. Urine bFGF levels have been shown to correlate with tumor stage (155) and with local recurrence in UC patients (156). p53 plays a key role in angiogenesis. Rev. and it plays a critical role in epithelial cell-cell adhesion. Expression of TP messenger RNA in invasive UC is 33-fold higher than in superficial tumors and 260-fold higher than in normal bladder (149). as well as to their spreading to adjacent and distant sites. The enzyme thymidine phosphorylase (TP) promotes the production of interleukin-8 and the MMPs (148). P582S and A588T.ARI 9 December 2008 15:4 significantly correlated with poor prognosis in UC. Downloaded from arjournals. p53 upregulates TSP1. a potent angiogenesis inhibitor.

it also argues that TIMPs may not be reliable prognostic indicators. however. Tissue inhibitors of metalloproteinases (TIMPs). Although studies have reported poor prognosis in patients with high MMP-2:TIMP-2 ratios (174. In fact. The tumor’s ability to degrade the matrix and invade the basement membrane is facilitated by the actions of several protease families.annualreviews. this finding is not consistent (176). molecular diagnostics have only recently forayed into the field of UC detection. Downloaded from arjournals. although the harsh urinary pH degrades most proteases. Molecular Tests That Identify Cancer Markers in Urine Molecular diagnostic tests for UC essentially identify tumor-associated antigens or genetic alterations in tumor cells exfoliated in urine. They are receptors for ECM proteins such as laminin and collagen. as hematuria detection lacks specificity.annualreviews. 171). and muscle-invasive UCs show either a loss of α6β4 and/or collagen VII expression or a lack of colocalization of the two proteins (168). these need to be very sensitive and specific in detecting UC. if altered. the MMP-9:E-cadherin ratio is prognostic for disease-specific survival (173). ANRV368-PM04-11 ARI 9 December 2008 15:4 survival in UC patients (162–165). and many are exclusive to UC. those proteins that do survive are very specific for the urologic tract. In normal urothelial cells. can promote tumor progression.org by WIB6149 . The collection of exfoliated cells from voided urine that can identify tumor markers is the basis for cytologic examination and for various diagnostic molecular assays. www. Pathol. Furthermore.Annu. and metastasis. For personal use only. Additionally. Nevertheless.org • Bladder Cancer 269 . Patients with tumors that exhibit weak α6β4 immunoreactivity perform significantly better than do those with either no expression or strong overexpression (169).and process-specific approach. proteins produced by the host or the tumor itself. molecular markers of invasion are generally robust predictors of patient outcome in UC. thus linking the cytoskeleton to the ECM.U. Rev. This has stemmed from the need to provide rapid. MOLECULAR DIAGNOSTIC TESTS FOR BLADDER CANCER Although most of the above discussion focuses on the identification and use of markers for disease prognosis. Advantages of Urine as a Marker Source Diagnosis of UC should preferably be made using noninvasive procedures. thereby inhibiting tumor cell invasion. Dis. Although such paradoxical TIMP behavior may be explained as a response to elevated MMP levels (161).S. and they maintain normal tissue architecture (167). DRESDEN on 11/13/09. the α6β4 integrin has a close relationship to collagen VII.B. and MMP-2 overexpression can predict poor relapse-free and disease-specific survival (172). The α6β4 integrin is the most commonly studied in bladder tumorigenesis. and inexpensive diagnostic tests for UC. noninvasive. 2009. which. Loss of polarity of α6β4 expression has been noted in superficial UC. reliable. antagonize MMP function.4:251-285. loss of immunoreactivity of both Ecadherin and β-catenin is a strong predictor of poor progression-free and overall survival in UC (166). Furthermore. diagnostic markers can identify more general molecular characteristics of tumors. High levels of MMP-2 and MMP-9 have been associated with increasing stage and grade of UC (170. invasion. increased TIMP-2 expression has also been associated with worse prognosis (177). and urine functions as an excellent source of surrogate molecular markers for the disease because very few organs are exposed to it (as opposed to blood). Mech. The intracellular domains also connect to the actin cytoskeleton. especially the uPAs and MMPs. 175).L. and routine cystoscopies are both invasive and expensive (6). Integrins are transmembrane glycoprotein heterodimers that regulate cellular processes. a component of the hemidesmosomal anchoring complex. and it restricts cell migration by anchoring contacts with laminin. Although development of prognostic markers is based on a pathway.

and clotting factors. Urinary levels of cytokeratins 8 and 18 are measured by two urinary bladder cancer (UBC) quantitative assays: UBCTM II ELISA and UBCTM IRMA.ANRV368-PM04-11 ARI 9 December 2008 Annu. Rev. and it is expected that lowering the cut-off limit will increase sensitivity at the cost of specificity (6). Cytokeratins are intermediate filament proteins that are components of the epithelial cellular cytoskeleton. fibrinogen. For personal use only. BTA TRAK® has a sensitivity between 52% and 83% (6). or polymerase chain reactions (PCRs) (Table 3). Nuclear matrix protein 22 (NMP22) serves as a nuclear scaffold and is an important mitotic regulator that is overexpressed in UC. Dis.4% and specificities between 87% and 100% (6).7% to 70% (185). BLCA-4. and proliferation and promotes tumor progression and metastasis. Studies have reported sensitivities between 80% and 96. Because fibrinogen is present in blood. the HA-HAase test) . and the NMP22® test kit is a quantitative ELISA. As NMP22® is released from dead and dying urothelial cells and is also abundantly present in leukocytes. which results in leakage of serum proteins including plasminogen. Although the reported sensitivity of BTA stat® is extremely variable (9. Hyaluronidase (HAase) cleaves HA into small fragments that promote tumor angiogenesis. migration. Downloaded from arjournals.4:251-285. High VEGF levels in UC cells increase vascular permeability. and function to human complement factor H (hCFH). The combined sensitivity for both tests (collectively. enzyme-linked immunosorbent assays (ELISAs). structure. The combination of cystoscopy with NMP22® BladderChek® is more sensitive in detecting recurrent UC than either test or cytology individually.7%. different studies have used different cut-off limits (3. respectively (186). a single-step. Clotting factors convert plasminogen to plasmin and fibrinogen to fibrin.6–12 U ml−1 . Pathol. Urinary fibrin and FDP are measured by Accu-Dx® (formerly known as AuraTek FDP®).3%–89%). 183).B. BTA stat® is a point-of-care qualitative immunoassay. The NMP22® BladderChek® test is a qualitative point-of-care immunoassay that detects urine NMP22. Urinary hCFHrp inhibits the detection of hCFH by the tests. manufacturer cut-off 10U ml−1 ). is found throughout the urothelium (both tumor and adjacent normal) in UC patients exclusively (6). and bowel interposition can cause a false positive reading (182. Although the reported sensitivity of the NMP22® test kit is more variable than the specificity (Table 3).S. Variations of the ELISA have been used to detect the presence of BLCA4 in the urine. and BTA TRAK® is a quantitative ELISA. The reported sensitivity and specificity of NMP22® BladderChek® in UC detection are 55. Hyaluronic acid (HA) is a nonsulfated glycosaminoglycan that regulates cell adhesion.U. Urinary levels of HA and HAase are measured by two similar ELISA-like assays. the NMP22® test kit is more sensitive in detecting UC with a bilharzial etiology Mitra · Cote (178. Identification of urotheliumspecific cytokeratins in the urine can therefore serve as surrogate markers for UC. respectively (179). another protein component of the nuclear matrix. The sensitivity of the UBCTM tests varies from 48.annualreviews.org by WIB6149 . and this combination of positive and negative signals regulates their sensitivity. Plasmin can further degrade fibrin to fibrin degradation products (FDPs) (184). 2009. point-of-care gold-dye particle immunoassay. as well as specialized tests that are conducted in reference laboratories and that may require microscopic image analysis.L.7% and 85. the test may be falsely positive in individuals with benign urologic pathologies that cause hematuria. The bladder tumor antigen (BTA) assays detect human complement factor H–related protein (hCFHrp) in the urine that is similar in composition. as well as cystoscopy and cytology combined (180). urolithiasis. 181). but it could be as low as 25% and 13% for low-stage and low-grade UC. DRESDEN on 11/13/09. many benign urologic pathologies such as inflammation. Urologic pathologies that can cause hematuria often give false positive results due to high hCFH concentrations in the serum. Like BTA TRAK®. BTA TRAK® is reportedly more sensitive in detecting bilharzial-related UC (178). ELISA: enzymelinked immunosorbent assay 270 15:4 These include point-of-care tests that can be performed in the urologist’s office and require minimal to no training. Mech.

studies have concluded that using diagnostic marker panels (or markers in conjunction with cytology or cystoscopy) can increase the sensitivity versus using single markers alone. 63. and slides showing more than 5% positive cells for Lewis X are considered positive. However. Mech.org • Bladder Cancer 271 .4:251-285. 2009. ImmunoCytTM is an immunocytofluorescence test that uses monoclonal antibodies to detect a glycosylated form of carcinoembryonic antigen and mucin glycoproteins on exfoliated UC cells. For example. the catalytic subunit of telomerase. Downloaded from arjournals. Dis. the use of dissimilar microsatellite markers in different studies limits the comparison of the test across studies. respectively. 192). Schroeder et al.B. BTA stat®. The UroVysionTM test is a multitarget.annualreviews.25 to 1 year in 41% to 89% of patients under surveillance. It is visualized in exfoliated tumor cells by an immunocytochemical assay using anti–Lewis X monoclonal antibody.S.U. The criteria for detecting UC are (a) ≥ 5 cells with a gain of ≥ 2 chromosomes. Lewis X is the most commonly studied UCassociated glycoprotein antigen. Telomerase activity is measured by the telomeric repeat amplification protocol assay. 7.3%. interobserver variability. (b) ≥ 10 cells with a gain of 1 chromosome. Hautmann et al. NMP22®. The sensitivity of both assays is between 70% and 100% (186). (188) also noted that the sensitivity and specificity for the HAHAase test were equal to or better than those for cytology.3%. The detection of microsatellite alterations requires a ratio of tumor DNA to contaminating normal DNA of more than 0. A potential advantage of this test is its apparent ability to detect occult tumors that are not initially visible via cystoscopy (6). benign conditions such as urinary tract infections and severe inflammation can cause false positive results. As with prognostic markers. A minimum evaluation of 500 epithelial cells is required.org by WIB6149 . Pathol. multicolor fluorescent in situ hybridization assay that uses pericentromeric enumeration probes to detect aneuploidy for chromosomes 3. thereby imparting cellular immortality. Microsatellite alterations in UC are detected by PCR. need for constant quality control. Combining ImmunoCytTM in standard urinary cytology protocol can increase sensitivity (to approximately 86% to 90%) without significant loss in specificity (6).3%. which involves (a) PCR amplification of a telomeric template by telomerase present in exfoliated cells and (b) analysis by a telomerase PCR ELISA kit or real-time PCR (6). the combination of the HA-HAase test with ImmunoCytTM resulted in a sensitivity of 93. and UroVysionTM . its specificity is lower (191. it additionally uses a locus specific identifier to detect loss of the 9p21 locus. or (c) ≥ 20 cells with a loss of the 9p21 locus. Because telomerase is expressed in proliferating cells and leukocytes. For personal use only. Lewis X immunocytology of two consecutive urine samples instead of one can increase the sensitivity by almost 15% (189. hematuria detection and UBCTM . thereby limiting the clinical application of this diagnostic tool. (193) noted that although the individual sensitivities of the HA-HAase test. wherein a panel of multiple microsatellite markers (15–20 loci on different chromosomes) are tested on exfoliated UC cells and compared with corresponding sequences in peripheral lymphocytes. ImmunoCytTM . a ribonuclease-protein complex that adds telomeres to the 5 chromosomal ends.3%. by reverse-transcriptase PCR. and 17.Annu. DRESDEN on 11/13/09. A related assay measures the messenger RNA levels of human telomerase reverse transcriptase. However. Although some reports have indicated that the test has higher sensitivity than BTA stat®. At least 100 cells are required for evaluation. When both tests were combined with www.5% to 25% (186). 190). a steep learning curve. and 73. Chromosomal abnormalities detected in exfoliated cells in urine have preceded cystoscopically identifiable UCs by 0. represents yet another surrogate UC marker. and a relatively high testfailure rate due to inadequate specimen cellularity need to be overcome to improve general acceptance of this test. Telomerase.L. Rev. and cytology for UC detection were 83. ANRV368-PM04-11 ARI 9 December 2008 15:4 is higher than the individual sensitivities for each test (187).annualreviews. and presence of one fluorescent cell constitutes a positive test.

annualreviews. Inc. Mech.b (Matritech.3–89 70–88. Cortlandt Manor. urogenital tuberculosis UTI. detects hCFHrp Quantitative microplate sandwich ELISA.7–70 80–96. radiation cystitis.b (Polymedco. 2009. detects hCFHrp BTA stata..and high-grade/ -stage tumors No urine stabilization required Sensitive in detecting high-stage and bilharzial-related tumors Sensitive in detecting high-grade/-stage and bilharzial-related tumors Sensitive in detecting high-stage and bilharzial-related tumors Sensitive in detecting high-grade/-stage tumors Advantages UTI UTI. Downloaded from arjournals.7 9.4 48–100 52–83 68–70 55. Cortlandt Manor. NY) NMP22a. bladder inflammation.. DRESDEN on 11/13/09. BPH False positives Poor detection sensitivity for low-stage/-grade tumors Requires urine stabilization before transportation Antibodies cross-react with hCFH Test spot may darken upon drying.8 72–95 87–100 70–91 50–90 68–86 85.b (Matritech. Inc.b (Polymedco. calculi.4:251-285. calculi. giving a false positive result Lacks quantitation Antibodies cross-react with hCFH Disadvantages 9 December 2008 Specialized Qualitative immunoassay..B. MA) BLCA-4 UBC II ELISAb .7 50–90 Specificity (%) Sensitive in detecting both low. UBC IRMAb (IDL Biotech. bowel interposition UTI. NY) Point-of-care Principle Detection Sensitivity (%) Molecular diagnostic tests for bladder cancer ARI Test Table 3 Annu. For personal use only. MA) · Cote Accu-Dxa (PerImmune Inc.org by WIB6149 . detects NMP22 Immunoblot.U.S.272 Mitra Qualitative immunoassay.. Pathol. detects fibrin and FDP NMP22 BladderCheka. Dis.L. Newton. Rev. detects NMP22 Qualitative immunoassay. quantitative ELISA Quantitative solid-phase sandwich monoclonal assay Quantitative ELISA. BPH Microhematuria. Inc. Inc. ANRV368-PM04-11 15:4 . Rockville. Newton. calculi. Sweden) HA-HAase 91–100 48. calculi.. MD) Quantitative ELISA. detects HA and HAase BTA TRAKa. Bromma. bowel interposition UTI.

Telomerase PCR ELISA kit or real-time PCR. HAase. reverse transcriptase polymerase chain reaction. ELISA.annualreviews. Pathol. RT-PCR. UTI. detects Lewis X antigen Immunocytofluorescence.org • Bladder Cancer 60–70 36. hTERT. Sensitivity affected by TRAP degradation in urine and by sample collection and processing errors b Approved by the U.. enzyme-linked immunosorbent assay. Quebec.4 69–87 72–97 60–70 60–70 Specificity (%) 9 December 2008 70–100 70–100 Sensitivity (%) ARI a Principle Test Detection Annu. Rev. human complement factor H.4 89–96 80–100 Increased sensitivity with cytology without significant loss of specificity Sensitive in detecting high-grade/-stage tumors Sensitive in detecting CIS. Inc. 70–80 79. Canada) www. measures hTERT mRNA levels PCR Multitarget. Commercially available.B. TRAP. involves PCR amplification of a telomeric template by telomerase RT-PCR. hyaluronidase. HA. FDP.4:251-285. hCFH. detects a glycosylated form of carcinoembryonic antigen and mucin glycoproteins TRAP hTERT Microsatellite analysis UroVysiona. Abbreviations: BPH. benign prostatic hyperplasia.annualreviews.L.S.8–94. Dis. BPH Reactive urothelial lesions UTI. UTI. human telomerase reverse transcriptase. hCFHrp. severe urinary tract inflammation UTI. urine fixation required Antigen also expressed by benign umbrella cells of urothelium Lower sensitivity for low-grade/-stage tumors Requires highly trained personnel and sophisticated equipment Sensitivity affected by hTERT degradation in urine and by sample collection and processing errors Needs at least 50 telomerase-expressing cells to yield a positive result. Downloaded from arjournals. DRESDEN on 11/13/09. hyaluronic acid. telomeric repeat amplification protocol. severe urinary tract inflammation Disadvantages Bladder washings cannot be used. Des Plaines. For personal use only.b (Abbott Molecular.. fibrin degradation product. multicolor fluorescent in situ hybridization assay Immunocytochemistry. Inc.S.9–86. high-grade. and occult tumors Advantages False positives Microhematuria. BPH UTI. ANRV368-PM04-11 15:4 273 . 2009. IL) Lewis X ImmunoCyta.org by WIB6149 . Mech.U. Food and Drug Administration for bladder cancer diagnosis/management. hCFH-related protein.b (DiagnoCure. urinary tract infection.

respectively. 274 Mitra · Cote . cell growth. 5.S. The availability of sophisticated genomic. Recent studies have adopted pathway-specific approaches to identify alterations in cellular processes in UC that. thus necessitating intense and often expensive surveillance and patient follow-up. in turn. In addition to the individually prognostic markers that have been identified in several pathways involved in bladder tumorigenesis. can predict clinical outcome in individual patients. proteomic. and it is as much of an economic problem as it is a public health problem.annualreviews. this increase in sensitivity may occur at the cost of specificity. and statistical tools now offer us the possibility of assimilating existing data to establish diagnostic and prognostic marker panels that can then be validated in retrospective and prospective studies. the sensitivity increased to 96. Although we have tried to review the most significant pathways that control critical cellular process in urothelial cells. their respective specificities dropped from 98% and 62% to 61% in combination.B. 2009. CONCLUSION Scientists and clinicians now have an increased understanding of the risk factors and molecular alterations that contribute to bladder tumorigenesis and progression. and aniline dyes are the most important risk factors for UC. there are several other lesser-known and uncharacterized cellular pathways that may also contribute towards UC development. and gene regulation—is important in maintaining homeostasis of urothelial cells. Mech. cell death.U. signal transduction. For personal use only. However. 6.7%. For instance. Tˆetu et al. Molecular diagnostic tests for UC are able to detect tumors using urine as a noninvasive marker source. thereby leading to more false positive results. recent studies have identified prognostic panels comprising markers across multiple tumorigenic pathways. aromatic amines. Future studies will aim to identify these molecules and pathways and their impact on tumor behavior and prognosis. cytology. 2. SUMMARY POINTS 1. reaching optimal levels of sensitivity and specificity for most clinically approved tests is still a challenge. Arsenic exposure and Schistosoma haematobium infestation are also important factors in endemic areas. 3. 7. 4. Rev.4:251-285.L. Aberrations in one or more of these processes are responsible for malignant transformation of the urothelium. Exposure to tobacco smoke. However.ANRV368-PM04-11 ARI 9 December 2008 15:4 Annu. DRESDEN on 11/13/09. This has led to the identification and characterization of individ- ual markers and marker panels that can diagnose UC and predict prognosis. UC is the most common type of bladder tumor. The “extrinsic” processes of angiogenesis and tumor cell invasion are also responsible for tumor maintenance and progression. Pathol. computational. (194) reported that while the sensitivity of routine cytology and ImmunoCytTM in detecting recurrent UC increased from their individual levels of 29% and 74%.org by WIB6149 . Interaction of molecular pathways involved in the five “intrinsic” cellular processes— cell-cycle regulation. Dis. Downloaded from arjournals. to 84% in combination. Noninvasive bladder tumors generally have a more distinct set of molecular alterations and clinical behavior than the more aggressive invasive tumors.

org • Bladder Cancer 275 .S.org by WIB6149 .cancer.: SEER. However. inconsistent immunohistochemical staining criteria. For personal use only. many of which are already targets for novel therapeutics. Although many individual prognostic markers have been identified in UC. Botteman MF. Amin MB. Weinberg RA. DRESDEN on 11/13/09. Cell 100:57–70 www. This provides an impetus for initiation of clinical trials targeting patients with tumors that harbor specific molecular lesions with such therapeutics. 55:74–108 3. Clin. RJ Cote. Cote RJ. CA123027. CA71921–09. Whittier Foundation. Natl. and noninvasive point-ofcare tests. Surveillance Epidemiology and End Results (SEER) stat fact sheets: cancer of the urinary bladder. Global cancer statistics.annualreviews. DISCLOSURE STATEMENT The authors are not aware of any biases that might be perceived as affecting the objectivity of this review. N Weidner. 1. and variable outcome parameters. 2003. ed.K.html 4. 2009. Redaelli A. and will spur discovery of other novel compounds that can target additional molecular alterations. the Dhont Family Foundation. different cut-off points for determination of positivity. economical. Pashos CL. Pathol. Bray F. Reasons include differences in study designs and patient cohorts. Future studies need to validate the markers identified thus far in large prospective clinical cohorts by employing standardized study and analysis protocols. Dis. rather than combining markers without biologic rationale.4:251-285. Laskin B. 4.annualreviews. and EB008275. 2009. Philadelphia. 2005. LITERATURE CITED 1. Ferlay J. Bladder and urethra.B. the L.ANRV368-PM04-11 ARI 9 December 2008 15:4 FUTURE ISSUES Annu. efforts must made to generate concise prognostic marker panels that are pathway based. there is still a lack of consensus on which markers can be employed clinically. and the Candy Foundation. Downloaded from arjournals. The hallmarks of cancer. Rev. In press 2. Such panels will serve as robust clinical predictors while also providing further insight into the biologic mechanisms behind UC progression. PA: Saunders. Cancer Inst. Parkin DM. 2002. Hauser R. Identification of new diagnostic and prognostic markers is concomitantly generating a vast library of druggable targets in UC.gov/statfacts/html/urinb. 2000. 2. Cancer Inst. Concerted efforts must be made to identify reliable diagnostic markers that can be assessed by rapid. Molecular tests currently employed for UC detection either lack portability or suffer from lack of sensitivity and specificity. In Modern Surgical Pathology.L. Mech. S Suster. http://seer. CA Cancer J. Pharmacoeconomics 21:1315–30 5. 3. Natl. Mitra AP. The health economics of bladder cancer: a comprehensive review of the published literature. 2007. Studies have already started identifying prognostic panels that consist of multiple markers. LM Weiss. Hanahan D. Pisani P. The authors apologize to the investigators whose studies could not be appropriately cited due to space limitations.U. ACKNOWLEDGMENTS Research on bladder cancer in the authors’ laboratory is supported by National Institutes of Health/National Cancer Institute grant numbers CA86871.

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org by WIB6149 . Injury. 2009. Cho and Ie-Ming Shih p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287 v .S. Prognosis.AR368-FM ARI 8 December 2008 13:2 Annu.4:251-285. Pober. DRESDEN on 11/13/09. Contents Annual Review of Pathology: Mechanisms of Disease Volume 4.B. Asa and Shereen Ezzat p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p97 PTEN and the PI3-Kinase Pathway in Cancer Nader Chalhoub and Suzanne J. Bradley p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p71 The Pathogenesis of Pituitary Tumors Sylvia L. 2009 The First Fifty Years in Research Peter A. and Treatment Sara I. Downloaded from arjournals. Iacobuzio-Donahue p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 229 Molecular Pathogenesis and Diagnostics of Bladder Cancer Anirban P. For personal use only. Jens Stanelle.U.L. Baker p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 127 Pathogenesis of Classical and Lymphocyte-Predominant Hodgkin Lymphoma Roland Schmitz. Mech.annualreviews. Martin-Leo Hansmann. Mitchell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p19 Molecular Pathology of Head and Neck Cancer: Implications for Diagnosis. and Death Jordan S. Pai and William H. Mitra and Richard J. Dis. Cote p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 251 Ovarian Cancer Kathleen R. Teitell and Pier Paolo Pandolfi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175 MicroRNAs in Cancer Yong Sun Lee and Anindya Dutta p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 199 Epigenetic Changes in Cancer Christine A. Ward p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1 Graft Vascular Disease: Immune Response Meets the Vessel Wall Richard N. Wang Min. Westra p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49 Mechanisms of Endothelial Dysfunction. Pathol. and John R. Rev. and Ralf Küppers p p p p p p p p p p p p p 151 Molecular Genetics of Acute Lymphoblastic Leukemia Michael A.

and Eugene E. Venkitaraman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 461 Regulation of Hepcidin and Iron-Overload Disease Pauline L. Lemon p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 399 The Immunopathogenesis of Rheumatoid Arthritis John B. Mech. Pathol. Rev. Michael H. Lee and Ernest Beutler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 489 The Brainstem and Serotonin in the Sudden Infant Death Syndrome Hannah C. Richerson. Noffsinger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 343 Nod-Like Receptors: Role in Innate Immunity and Inflammatory Disease Grace Chen. Haluska p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 551 Indexes Cumulative Index of Contributing Authors. Downloaded from arjournals. Susan M.AR368-FM ARI 8 December 2008 13:2 Drosophila Models of Neurodegenerative Diseases Bingwei Lu and Hannes Vogel p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 315 Serrated Polyps and Colorectal Cancer: New Pathway to Malignancy Amy E. Kinney. Nattie p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 517 Molecular Pathogenesis of Cutaneous Melanocytic Neoplasms Nageatte Ibrahim and Frank G. Dymecki. Imboden p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417 The Pathology of Chronic Obstructive Pulmonary Disease James C. Shaw.L. Hogg and Wim Timens p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 435 Linking the Cellular Functions of BRCA Genes to Cancer Pathogenesis and Treatment Ashok R. Robert A. 2009. For personal use only.U.org vi Contents . DRESDEN on 11/13/09. and Gabriel Nunez ˜ p p p p p p p p p p p p p p p p p p p p p p p 365 Annu. Volumes 1–4 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 581 Cumulative Index of Chapter Titles. Chromosomal Instability.B.4:251-285.S. Volumes 1–4 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 583 Errata An online log of corrections to Annual Review of Pathology. Darnall.org by WIB6149 . Mechanisms of Disease articles may be found at http://pathol. Yun-Gi Kim.annualreviews. Tumor Suppressors. McGivern and Stanley M. George B. Dis. and Hepatitis C Virus–Associated Liver Cancer David R.annualreviews.